Pediatric Neuroblastoma 3 8 16 Kuhn - Mayo Clinic · Pediatric Neuroblastoma • Embryonal neoplasm...
Transcript of Pediatric Neuroblastoma 3 8 16 Kuhn - Mayo Clinic · Pediatric Neuroblastoma • Embryonal neoplasm...
©2015 MFMER | slide-1
Pediatric Neuroblastoma:Pharmacotherapy Advances for High-Risk
and Relapsed/Refractory Disease
Alexis Kuhn, PharmDPGY2 Oncology Pharmacy Resident
Pharmacy Grand Rounds, March 8, 2016
©2015 MFMER | slide-2
Objectives
• Identify therapeutic options for the treatment of high-risk and relapsed/refractory pediatric neuroblastoma.
• Review clinical data evaluating the use of 131I-MIBG, ALK inhibitors, and GD2 antibodies in treatment regimens for high-risk and relapsed/refractory pediatric neuroblastoma.
• Outline therapeutic strategies to mitigate adverse events associated with dinutuximab-containing regimens.
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Case: KE
RLE: Right lower extremity
• KE is a 7 yo previously healthy female who presents w/ several “knots” on her scalp & orbit, a palpable large mass on RLE, & marked bruising
• Initial Workup:• CBC: Hgb 7.2, WBC 4.8, Plt 6, differential
unremarkable• CT: calcified right adrenal mass
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Case, Cont.
• Workup, cont.• Urine: VMA = 14.6, HVA = 40 • BMBx: >90% involvement w/ small blue
round cell tumors forming pseudorosettes• FISH: MYCN gene amplification
• Diagnosis:• Stage 4 neuroblastoma
VMA: vanillylmandelic acidHVA: homovanillic acidBMBx: bone marrow biopsyFISH: fluorescence in situ hybridization
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Outline
• Neuroblastoma 101
• Novel options for upfront management of high-risk disease• Dinutuximab• 131I-MIBG
• Novel options for relapsed/refractory disease• hu14.18K322A• 131I-MIBG• Small molecule inhibitors (crizotinib, alisertib)
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Pediatric Neuroblastoma
• Embryonal neoplasm of sympathetic nervous system
• 3rd most common pediatric cancer; most common extracranial solid tumor in children
• ~700 cases in US annually
• 90% will be diagnosed by 5 years of age• Median age of diagnosis: ~18 mo
Ward et al. CA Canc J Clin 2014; 64:83-103.Brodeur et al. Principles and Practice of Pediatric Oncology. 6th editionMaris. NEJM 2010; 362:2202-11.
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Clinical Presentation
• Majority present w/ primary abdominal disease• Fullness, discomfort, palpable mass
• Signs/symptoms of metastatic disease• Periorbital ecchymoses, proptosis• Bone pain, cytopenias• Bluish, nontender subcutaneous nodules
• Detectable urinary catecholamines (VMA, HVA)
Brodeur et al. Principles and Practice of Pediatric Oncology. 6th edition
VMA: Vanillylmandelic acidHVA: Homovanillic acid
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Clinical Presentation
• Majority present w/ primary abdominal disease• Fullness, discomfort, palpable mass
• Signs/symptoms of metastatic disease• Periorbital ecchymoses, proptosis• Bone pain, cytopenias• Bluish, nontender subcutaneous nodules
• Detectable urinary catecholamines (VMA, HVA)• Paraneoplastic syndromes
• Opsoclonus-myoclonus-ataxia syndrome• VIP syndrome
Brodeur et al. Principles and Practice of Pediatric Oncology. 6th edition
VIP: vasoactive intestinal polypeptideVMA: Vanillylmandelic acidHVA: Homovanillic acid
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Staging
INSS Stage
Proportionof Patients
Description
1 17% Local tumor w/ complete gross excision
2 16% Localized tumor w/ or w/o complete excision but positive ipsilateral node(s)
3 16% Unresectable unilateral tumor infiltrating across midline
4 44% Dissemination to distant nodes or organs
4S 7% Localized tumor w/ dissemination limited to skin, liver, and/or marrow in infants <1yr of age
Brodeur et al. Principles and Practice of Pediatric Oncology. 6th edition
INSS: International Neuroblastoma Staging System
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Prognosis
Risk Classification (COG)
Proportion of Patients Long-Term Event-Free Survival
Low 40% >95%Intermediate 20% 80-95%High 40% 40-50%
Brodeur et al. Principles and Practice of Pediatric Oncology. 6th editionIrwin et al. Pediatr Clin N Am 2015; 62:225-56.
Variable Poor PrognosticFactors
INSS Stage Higher stage disease (except 4S)
Age >12-18 mo Shimada Histology
Unfavorable
MYCN Amplification
Amplified
DNA Ploidy Diploid
INSS: International Neuroblastoma Staging SystemCOG: Children’s Oncology Group
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Treatment Overview: High-Risk Disease
Brodeur et al. Principles and Practice of Pediatric Oncology. 6th editionMaris. NEJM 2010; 362:2202-11.Pinto et al. J Clin Oncol 2015; 33(27):3008-17.
Induction Chemotherapy
Surgery
Myeloablative Therapy/
Autologous HSCT
Radiation
Maintenance Therapy
HSCT: Hematopoietic stem cell transplantation
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Historical Standard
Matthay et al. NEJM 1999; 341(16):1165-73.Matthay et al. J Clin Oncol 2009; 27(7):1007-13.
Induction chemotherapy
x 5 cycles
Ran
dom
izat
ion
#1
Chemo
Myeloablative Therapy +Autologous HSCT
Chemo Chemo Observe
RA x 6 cyclesR
ando
miz
atio
n #2
HSCT: Hematopoietic stem cell transplantationRA: 13-cis retinoic acid (isotretinoin)NS: non-significant
Design Intervention Patients EfficacyMatthayet al 1999
Multi-center, Phase 3randomized controlled trial
Randomization #1: Chemo vs auto HSCT Randomization #2: observation vs RA maintenance
N = 379 pts w/ newly dx high-risk neuroblastoma(N = 258 proceeded to randomization #2)
Randomization #1: 3yr EFS = 34% vs 22% (p = 0.034), 3yr OS = 43% vs 44% (p = NS)Randomization #2:3yr EFS = 46% vs 29% (p = 0.027),3yr OS = 56% vs 50% (p = NS)
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Self-Assessment #1
• Which of the following should be a part of KE’s initial treatment course for her high-risk neuroblastoma?
a. Crizotinibb. 131I-MIBGc. Alisertibd. Dinutuximab
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Outline
• Neuroblastoma 101
• Novel options for upfront management of high-risk disease• Dinutuximab• 131I-MIBG
• Novel options for relapsed/refractory disease• hu14.18K322A• 131I-MIBG• Small molecule inhibitors (crizotinib, alisertib)
©2015 MFMER | slide-15
Dinutuximab
GD2
ALK
NET
MYCN
Aurora A Kinase
NET: norepinephrine transporterVMA: vanillylmandelic acidHVA: homovanillic acidALK: anaplastic lymphoma kinase
Catecholamines
VMA HVA
Maris. NEJM 2010; 362:2202-11.Pinto et al. J Clin Oncol 2015; 33(27):3008-17.Poessl et al. Ann Pharmacol 2016; Epub ahead of print
Antibody-Dependent Cellular Cytotoxicity &Complement-Mediated Cytotoxicity
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GD2
• Disialoganglioside tumor-associated antigen• Tumor expression:
• Neuroblastomas, melanomas, others• Normal tissue expression:
• Neurons, melanocytes, peripheral sensory nerve fibers
• Dinutuximab binding triggers ADCC and complement-mediated cytotoxicity
Yu et al. NEJM 2010; 363(14):1324-34.Poessl et al. Ann Pharmacol 2016; Epub ahead of print
ADCC: Antibody-dependent cellular cytotoxicity
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Dinutuximab (ch14.18)
• Chimeric monoclonal antibody against GD2
• Approved 3/2015 for high-risk neuroblastoma• Combination therapy w/ GM-CSF, IL-2, and
13-cis retinoic acid (isotretinoin)
• Box warnings:• Life-threatening infusion reactions• Severe neuropathic pain
Yu et al. NEJM 2010; 363(14):1324-34.Poessl et al. Ann Pharmacol 2016; Epub ahead of printUnituxin™ [package insert]. Silver Spring, MD: United Therapeutics Corp; 2015
GM-CSF: granulocyte-macrophage colony stimulating factorIL-2: interleukin-2
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Dinutuximab Efficacy
Yu et al. NEJM 2010; 363(14):1324-34.
Induction, auto HSCT,
radiation
Ran
dom
izat
ion
RA
ch14.18 + RA + GM-
CSF
Design Intervention Patients EfficacyYu et al 2010
Multi-center, Phase 3randomized controlled trial
Standard RA maintenancevs dinutuximabimmuno-therapy
N = 226 pts w/ high-risk neuroblastomas/p auto HSCT w/o progressive disease
Stopped early for benefit;2yr EFS = 66% vs 46% (p = 0.01)2yr OS = 86% vs 75% (p = 0.02)
RA RA RA RA RA
ch14.18 + RA + IL-2
ch14.18 + RA + GM-
CSF
ch14.18 + RA + IL-2
ch14.18 + RA + GM-
CSFRA
ch14.18: dinutuximabRA: 13-cis retinoic acid (isotretinoin)GM-CSF: granulocyte-macrophage colony stimulating factorIL-2: interleukin 2
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Dinutuximab Safety
Yu et al. NEJM 2010; 363(14):1324-34.APAP: acetaminophen
• Grade 3/4 pain = 52%• Improved with subsequent cycles• Premedicate w/ morphine bolus + infusion
• Capillary leak syndrome = 23%• Worse during cycles 2, 4
• Grade 3/4 hypersensitivity = 25%• Premedicate w/ APAP, diphenhydramine
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Pain Management
• PI guidance:• IV morphine 50 mcg/kg, followed by 20-50
mcg/kg/hr during infusion + 2 hours after• 25-50 mcg/kg boluses q2h PRN
• “Consider use of gabapentin or lidocaine”
• Dexmedetomidine?• Report of 6 pts receiving adjunctive
dexmedetomidine (avg dose 0.17 mcg/kg/hr)• Dinutuximab infusion rate interrupted only 1/122
treatment days• Hypotension 30%, hypoxemia 8%, bradycardia 4%
Poessl et al. Ann Pharmacol 2016; Epub ahead of printUnituxin™ [package insert]. Silver Spring, MD: United Therapeutics Corp; 2015Gorges et al. Pediatr Blood Cancer 2015; 62:29-34.
PI: package insert
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131I-MIBG
GD2
ALK
NET
MYCN
Aurora A Kinase
NET: Norepinephrine transporterVMA: Vanillylmandelic acidHMA: Homovanillic acidALK: anaplastic lymphoma kinase
Catecholamines
VMA HVA
Maris. NEJM 2010; 362:2202-11.Pinto et al. J Clin Oncol 2015; 33(27):3008-17.Streby et al. Pediatr Blood Cancer 2015; 62:5-11.
Cytotoxicity;Radiation-induced bystander effect
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131I-MIBG
• 90% tumors express norepinephrine transporter (NET)
• MIBG = norepinephrine analogue; actively transported intracellularly via NET
• TCAs may compete w/ MIBG uptake• Radiolabeled MIBG cytotoxicity• Hematologic toxicity; radiation precautions
MIBG: metaiodobenzylguanidineTCA: tricyclic antidepressant
Streby et al. Pediatr Blood Cancer 2015; 62:5-11.
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131I-MIBG EfficacyUpfront Therapy
Streby et al. Pediatr Blood Cancer 2015; 62:5-11.de Kraker et al. Eur J Cancer 2008; 44(4):551-56.Kraal et al. Pediatr Blood Cancer 2015; 62:1886-91.
Design Intervention Patients Efficacyde Krakeret al 2008
Singlecenter, Phase 1
131I-MIBG monotherapy
N = 44 pts w/ newly dx high-risk, MIBG-avid neuroblastoma
ORR = 66%;5yr EFS = 12.2%, 5yr OS = 14.6%
Kraal et al 2015
Multi-center, single-arm Phase 2
Upfront 131I-MIBG +topotecan
N = 16 pts w/ newly dx high-risk neuroblastoma
ORR = 57%; 10yr OS = 6%
MIBG: metaiodobenzylguanidineORR: objective response rate
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131I-MIBG SafetyUpfront Therapy
• de Kraker et al 2008• “Hematological side effects were limited to
thrombocytopenia”• 1 death attributed to toxic myelosuppression• Transient TSH elevations in 45.5% patients
• Kraal et al 2015• Grade 3/4 thrombocytopenia = 60%• Grade 3/4 neutropenia = 60%
Streby et al. Pediatr Blood Cancer 2015; 62:5-11.de Kraker et al. Eur J Cancer 2008; 44(4):551-56.Kraal et al. Pediatr Blood Cancer 2015; 62:1886-91.
MIBG: metaiodobenzylguanidineORR: objective response rate
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Case, Revisited
• After induction chemotherapy, surgical removal of her primary, autologous stem cell transplant, and radiation, KE is set to begin immunotherapy with dinutuximab.
• Which of the following pre-medication regimens would be most appropriate for dinutuximab?
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Self-Assessment #2
• Which of the following pre-medication regimens would be most appropriate for dinutuximab?
a. Ondansetron, dexamethasone, aprepitantb. Methylprednisolone, APAP,
diphenhydraminec. Morphine, APAP, diphenhydramine, IV
fluidsd. Allopurinol, IV fluids, granisetron
©2015 MFMER | slide-27
Outline
• Neuroblastoma 101
• Novel options for upfront management of high-risk disease• Dinutuximab• 131I-MIBG
• Novel options for relapsed/refractory disease• hu14.18K322A• 131I-MIBG• Small molecule inhibitors (crizotinib, alisertib)
©2015 MFMER | slide-28
hu14.18K322A
• Humanized GD2 antibody engineered to reduce pain
• K322A point mutation decreased complement activation
• Decreased complement activation decreased pain
Sorkin et al. Pain 2010; 149:135-42.Navid et al. J Clin Oncol 2014; 32:1445-52.
Design Intervention Patients EfficacyNavidet al 2014
Singlecenter, Phase 1trial; 3+3 dose-finding
hu14.18K322Amonotherapy
N = 39 pts w/ relapsed/ refractory neuroblastoma
MTD = 60 mg/m2; Response rates = 5% partial, 10% complete;Median duration of response = 3.4 mo
MTD: maximum tolerated dose
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hu14.18K322A Safety
• Grade 3/4 pain = 68%• Hypersensitivity = 2.5%• Capillary leak syndrome = 0% • Ocular/vision abnormalities = 51%
Navid et al. J Clin Oncol 2014; 32:1445-52.Anghelescu et al. Pediatr Blood Cancer 2015; 62:224-228.
Design Intervention Patients SafetyAnghelescu et al 2015
Chart review Dinutuximabvs hu14.18K322A
N = 9 pts on dinutuximab; N = 19 pts on hu14.18K322A
Median opioid reqs2.41 vs 1.57 mg/kg(p=0.019); no difference in anxiolytics
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131I-MIBGRelapsed/Refractory Disease
• Safety• Grade 3/4 thrombocytopenia = 62%• Grade 3/4 neutropenia = 46%
Matthay et al. J Clin Oncol 1998; 16(1):229-36.
Design Intervention Patients EfficacyMatthayet al 1998
Singlecenter, Phase 1
131I-MIBG monotherapy
N = 30 pts w/ relapsedneuroblastoma
30% partial response, 3% complete response;Median OS 6 mo
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Small Molecule Inhibitors
GD2
ALK
NET
MYCN
Aurora A Kinase
NET: Norepinephrine transporterVMA: Vanillylmandelic acidHVA: Homovanillic acidALK: anaplastic lymphoma kinase
Catecholamines
VMA HVA
Maris. NEJM 2010; 362:2202-11.Mosse et al. Lancet Oncol 2013; 14:472-80.DuBois et al. J Clin Oncol 2016; ePubahead of print
Crizotinib
Alisertib
©2015 MFMER | slide-32
Small Molecule Inhibitors
• ALK mutation most common cause of hereditary neuroblastoma
• Found in 7-10% sporadic cases• Crizotinib = ALK inhibitor; approved 8/2011
for NSCLC• Increased Aurora A kinase expression
correlates w/ inferior outcomes• Inhibition may result in MYCN destabilization• Alisertib = Aurora A kinase inhibitor;
investigational agent Mosse et al. Lancet Oncol 2013; 14:472-80.DuBois et al. J Clin Oncol 2016; ePubahead of print
ALK: anaplastic lymphoma kinaseNSCLC: non-small cell lung cancer
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Small Molecule Inhibitor Efficacy
Design Intervention Patients EfficacyMosse et al 2013
Multi-center, Phase 1
Crizotinibmonotherapy
N = 34 pts w/ relapsed/ refractory neuroblastoma
MTD = 280 mg/m2;ORR 29.3% (5.8% complete response, 23.5% stable disease)
DuBoiset al 2016
Multi-center, Phase I
Alisertib + irinotecan + temozolomide
N = 22 pts w/ relapsed/ refractory high-risk neuroblastoma
MTD = 60 mg/m2;ORR 31.8% (22.7% complete response, 9.1% partial response);2yr PFS = 52.4%
Mosse et al. Lancet Oncol 2013; 14:472-80.DuBois et al. J Clin Oncol 2016; ePubahead of print
MTD: maximum tolerated doseORR: objective response ratePFS: progression-free survival
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Small Molecule Inhibitor Safety
• Crizotinib• Grade 3/4 neutropenia = 12.7%• Grade 3/4 transaminitis = 2.5%• Visual disturbances = 37%
• Alisertib• Any grade thrombocytopenia = 20%• Any grade neutropenia = 22%
• Myeloid growth factor support • Any grade diarrhea = 22%
• Cephalosporin prophylaxisMosse et al. Lancet Oncol 2013; 14:472-80.DuBois et al. J Clin Oncol 2016; ePubahead of print
©2015 MFMER | slide-35
Case, Revisited
• 6 months after completion of immunotherapy, KE notes a large, palpable mass in her abdomen, concerning for relapse.
• Which of the following treatment modalities exhibited the highest response rates in relapsed/refractory disease?
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Self-Assessment #3
• Which of the following treatment modalities exhibited the highest response rates in relapsed/refractory disease?
a. 131I-MIBG monotherapyb. Crizotinib monotherapyc. Alisertib combination therapyd. hu14.18K322A monotherapy
©2015 MFMER | slide-37
Pediatric Neuroblastoma:Pharmacotherapy Advances for High-Risk
and Relapsed/Refractory Disease
Alexis Kuhn, PharmDPGY2 Oncology Pharmacy Resident
Pharmacy Grand Rounds, March 8, 2016
©2015 MFMER | slide-38
Dinutuximab Pain Management Algorithm
Morphineinfusion
Patient above pain
goal?
Yes
No
Continue current rate
Maximize morphine
infusion rate
Patient above pain
goal?
Slow dinutuximabinfusion rate
Yes
No
Patient above pain
goal?
Yes
No
Add adjuncts: gabapentin,
dexmedetomidine, lidocaine
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Conclusions
• Dinutuximab is standard of care for high-risk neuroblastoma
• Pain management!
• 131I-MIBG has been studied in upfront and relapsed/refractory settings
• Promising response rates, but technical difficulties
• Small molecule inhibitors have been studied in relapsed/refractory setting
• Alisertib appears to be promising JAM23
Slide 39
JAM23 why do you think this since it was given in combination and to newly diagnosed patients. I would expect the response rate to be higher. Julianna A Merten, 3/3/2016
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Tumor Biology
GD2
ALK
NET
MYCN
Aurora A Kinase
NET: Norepinephrine transporterVMA: Vanillylmandelic acidHVA: Homovanillic acidALK: anaplastic lymphoma kinase
Catecholamines
VMA HVA
Maris. NEJM 2010; 362:2202-11.Pinto et al. J Clin Oncol 2015; 33(27):3008-17.