1. Mini-HCVD + Inotuzumab Ozogamicin as Frontline Therapy in Older Adults With ALL
New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
This program is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, Seattle Genetics, and Takeda Oncology.

2. Inotuzumab Ozogamicin in ALL: Background
Inotuzumab ozogamicin, humanized monoclonal antibody[1]
Binds cell surface receptor CD22 with subnanomolar affinity
After binding, cytotoxin calicheamicin released into cell, inducing apoptotic response
Inotuzumab effective in relapsed/refractory ALL
58% ORR with median OS of 6.3 mos in highly treatment-experienced population[2]
Phase III study of inotuzumab vs BAT: ORR 81% vs 33%, respectively[3]
Older pts with ALL have worse outcomes due to drug toxicity
Current study evaluated safety and efficacy of reduced-dose HCVD + inotuzumab as frontline therapy in older adult pts with ALL
ALL, acute lymphocytic leukemia; BAT, best available therapy; HCVD, hyperfractionated cyclophosphamide, vincristine, doxorubicin.
1. Ohanian M, et al. Expert Opin Biol Ther. 2015;4: Kantarjian H, et al. Cancer. 2013;119: DeAngelo DJ, et al. EHA Abstract LB2073.
Slide credit: clinicaloptions.com

3. Frontline Mini-HCVD + Inotuzumab in Older ALL Pts: Phase II Study
Intensive Phase: 4 cycles
N = 38
4 cycles
Pts with ALL ≥ 60 yrs of age; ECOG PS 0-3; Bilirubin ≤ 1.5 mg/dL; ALT and AST < 3 x ULN; Creatinine ≤ 2 mg/dL
Cyclophosphamide 150 mg/m2 x 6
Dexamethasone 20 mg
Methotrexate 250 mg/m2
Cytarabine 0.5 g/m2 x 4
Inotuzumab on Day 3*
Intrathecal chemotherapy Days 2,8
If CD20+, Rituximab on Days 2,8
Cyclophosphamide 150 mg/m2 x 6
Dexamethasone 20 mg
Methotrexate 250 mg/m2
Cytarabine 0.5 g/m2 x 4
POMP maintenance phase (3 yrs)
ALL, acute lymphocytic leukemia; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECOG, Eastern Cooperative Oncology Group; Mini-HCVD, cyclophosphamide, dexamethasone, methotrexate, cytarabine; POMP, 6-mercaptopurine; vincristine, methotrexate, prednisone; PS, performance status; ULN, upper limit of normal.
*First cycle: Inotuzumab 1.3 mg/m2 in first 6 pts and pts 35 and beyond; 1.8 mg/m2 in pts 7-34.
Cycles 2-4: Inotuzumab 0.8 mg/m2 in first 6 pts; 1.3 mg/m2 in pts 7-34; 1.0 mg/m2 for pts 35 and beyond.
Study endpoints: PFS, response rate, OS, safety
Slide credit: clinicaloptions.com
Jabbour E, et al. ASH Abstract 83.

4. Mini-HCVD + Inotuzumab
Frontline Mini-HCVD + Inotuzumab in Older ALL Pts: Baseline Characteristics
Characteristic
Mini-HCVD + Inotuzumab
(N = 38)
Median age, yrs (range)
69 (60-79)
Male, n (%)
23 (61)
Median WBC at diagnosis, cells x 109/L (range)
3.5 ( )
WBC ≥ 50 cells x 109/L, n (%)
3 (8)
Karyotype, n (%)
Complex
Diploid
Intermediate
Miscellaneous
15 (39)
13 (34)
5 (13)
Median CD22 expression (range)
97 (72-100)
CD20 expression ≥ 20%, n (%)
22 (65)
ALL, acute lymphocytic leukemia; ECOG, Eastern Cooperative Oncology Group; Mini-HCVD, cyclophosphamide, dexamethasone, methotrexate, cytarabine; WBC, white blood cell.
Slide credit: clinicaloptions.com
Jabbour E, et al. ASH Abstract 83.

5. Frontline Mini-HCVD + Inotuzumab in Older ALL Pts: Response
Response, n (%)
Mini-HCVD + Inotuzumab
(N = 35*)
ORR
34 (97) CR
CR without platelet recovery
28 (80)
6 (17)
No response
1 (3)
Death within 4 wks of treatment
Cytogenetic complete response (n = 19 with abnormal karyotype)
19 (100)
Negative MRD status†
By Day 21
Overall‡
21/28 (75)
36/36 (100)
ALL, acute lymphocytic leukemia; Mini-HCVD, cyclophosphamide, dexamethasone, methotrexate, cytarabine; MRD, minimal residual disease.
*3 pts enrolled in study with CR on previous therapy.
†Assessed by 6-color multiparameter flow. 6 pts not evaluable.
‡All pts with morphologic response.
Slide credit: clinicaloptions.com
Jabbour E, et al. ASH Abstract 83.

6. Frontline Mini-HCVD + Inotuzumab in Older ALL Pts: Grade 3/4 AEs in ≥ 10%
Event, %
Mini HCVD + Inotuzumab
(N = 38)
Prolonged thrombocytopenia (> 6 wks) 74
Infection during consolidation
Infection during induction 53
Hyperglycemia 50
Hypokalemia 37
ALT/AST elevation 24
Hyperbilirubinemia 21
Hemorrhage 16
Diarrhea 11
Lipase elevation
ALL, acute lymphocytic leukemia; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Mini-HCVD, cyclophosphamide, dexamethasone, methotrexate, cytarabine.
Slide credit: clinicaloptions.com
Jabbour E, et al. ASH Abstract 83.

7. Frontline Mini-HCVD + Inotuzumab in Older ALL Pts: Hepatic SOS
Sinusoidal obstruction syndrome occurred in 4 pts
Parameter
Pt 1
Pt 2
Pt 3*
Pt 4
Age, yrs 63 67 68 70
No. of cycles completed (day in cycle)
3 (57)
2 (40) 4
2 (70)
SOS grade 2 5†
Status at time of report
Alive
Died
Died‡
*Previous allogeneic stem cell transplantation.
†Switched to mini-HCVD and rituximab. Received 2 additional courses, developed MOF and died.
‡SOS resolved; subsequently died from MOF after allogeneic stem cell transplantation.
ALL, acute lymphocytic leukemia; Mini-HCVD, cyclophosphamide, dexamethasone, methotrexate, cytarabine; MOF, multiple organ failure; SOS, sinusoidal obstruction syndrome.
Slide credit: clinicaloptions.com
Jabbour E, et al. ASH Abstract 83.

8. Frontline Mini-HCVD + Inotuzumab in Older ALL Pts: Other Outcomes
CR at 2 yrs: 81%
OS at 2 yrs: 64% (24/38)*
OS vs Regimen From Earlier Trial
Mini-HCVD + Inotuzumab ± Rituximab
HCVAD ± Rituximab
Median OS, mos 35 16
OS at 2 yrs, %† 64 38
ALL, acute lymphocytic leukemia; CRp, complete response without complete platelet recovery; ESRD, end-stage renal disease; GVHD, graft-vs-host disease; HCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; Mini-HCVD, cyclophosphamide, dexamethasone, methotrexate, cytarabine; MOF, multiple organ failure; PD, progressive disease; SCT, stem cell transplantation; SOS, sinusoidal obstruction syndrome.
*9 pts died in CR/CRp: 3 sepsis, 2 SOS, 1 gunshot, 1 dementia, 1 ESRD, 1 unknown cause. 1 pt resistant, died of PD; 4 pts relapsed, 3 died of PD; 1 pt with allogeneic SCT died of GVHD/sepsis/ MOF.
†P = .09
Jabbour E, et al. ASH Abstract 83.
O’Brien S, et al. Cancer. 2008;113:
Slide credit: clinicaloptions.com

9. Frontline Mini-HCVD + Inotuzumab in Older ALL Pts: Conclusions
Combination reduced-dose chemotherapy (mini- HCVD) with targeted therapy (inotuzumab) safe and effective in elderly pts with newly diagnosed ALL
SOS noted in 10% of pts
SOS of mild intensity reversible
Lower doses of inotuzumab being investigated
Early results appear to be better than those achieved with chemotherapy only
Study investigators concluded that inotuzumab ozogamicin should continue to be investigated as frontline therapy for ALL in older adults
ALL, acute lymphocytic leukemia; Mini-HCVD, cyclophosphamide, dexamethasone, methotrexate, cytarabine; SOS, sinusoidal obstruction syndrome.
Slide credit: clinicaloptions.com
Jabbour E, et al. ASH Abstract 83.

10. Go Online for More CCO Coverage of ASH 2015!
Short slideset summaries of all the key data
Additional CME-certified analyses with expert faculty commentary on all the key studies in:
Acute leukemias/chronic leukemias
Myeloma/plasma cell disorders
Lymphomas
MDS and myeloproliferative neoplasms
clinicaloptions.com/oncology