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3721 Salvage Chemotherapy with Inotuzumab Ozogamicin (INO) Combined with Mini-Hyper-CVD for Adult Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Acute Lymphoblastic Leukemia: Clinical Studies
Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster III
Monday, December 7, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Koji Sasaki, MD1, Hagop M. Kantarjian, MD2, Susan O'Brien, MD2, Deborah A Thomas, MD2, Farhad Ravandi, MD2, Guillermo Garcia-Manero, MD2, Tapan Kadia, MD3, Nitin Jain, MD2, Marina Konopleva, MD, PhD4, Zeev Estrov, M.D.2, Koichi Takahashi, MD2, Maria R. Khouri5*, Jovitta Jacob, RN2*, Rebecca Garris2*, Jorge E. Cortes2 and Elias Jabbour2

1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
4Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
5Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX

Background:Outcome of patients with R/R ALL is very poor. INO is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in R/R ALL with a response rate of 58% and median survival of 6.3 months. The addition of non-myelosuppressive therapy to effective low-intensity chemotherapy might further improve clinical outcome.

Methods: Patients ≥18 years with R/R ALL were eligible. The chemotherapy was lower intensity than conventional hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). Rituximab and intrathecal chemotherapy were given for first 4 courses. IO was given on Day 3 of each of the first 4 courses. Patients received INO at 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles.

Results: Forty-eight patients (23 men, 25 women) have been enrolled so far. Patient characteristics and outcome are summarized in Table 1.  Median age is 35 years (range 9-87). Median follow-up is 9.4 months (range, 1-27), and patients received a median of 2 cycles (1-8). Of 46 evaluable patients (2 patients, too early to assess response), 5 patients (11%) were refractory to mini-hyper-CVD + INO and died of progressive disease. Early death was encountered in 7 (15%) patients. The overall response rate was 74%: 24 (52%) CR, 8 (17%) CRp, and 2 (4%) marrow CR. Grade 3-4 non-hematological toxicities included infections, mucositis, increased LFTs, and VOD (n=6; 1 in a patient who had prior allo-SCT; 1 at D35 of CAR T-cell; and 3 post allo-SCT following INO therapy). Four (9%) patients were switched early to maintenance therapy due to poor performance status (n=1), infectious complications (n=2), and prolonged myelosuppression (n=1). Nineteen (41%) patients proceeded to receive allo-SCT. At the last follow-up, 20 (43%) patients are alive in response; 2 (4%) too early to assess response; 4 (8%) relapsed post transplantation. 22 (43%) patients died: 7 early death; 5 refractory disease; 5 post relapse after subsequent salvage, 1 post-transplantation VOD, 3 due to post-transplant complications, and 1 in response to IO due to sepsis and multiple organ failure. The 1-year PFS and OS rates were 60% and 46%, respectively. Median survival for patients with CR/CRp/marrow CR was 18 months versus 1 month in patients with refractory disease (p<0.001). Median survival was 17 months in patients with S1, 6 months in patients with S2 and 7 months in patients with S3+ (Figure).

Conclusions: The combination of INO with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with R/R ALL. The risk of VOD should be considered carefully for patients with previous liver damage and transplant candidate. Lower dose schedule of INO are being explored.

Table 1. Patient characteristics and outcome

Median (range) / No. (%)

N=48

Age (yrs)

35 [9-87]

Male

23 (48)

Performance Status (ECOG) ≥2

7 (15)

Salvage Status

   S1

     S1, Primary Ref

     S1, CRD1<12m

     S1, CRD1>12m

   S2

   >S3

24 (50)

4

11

9

11 (23)

13 (27)

Karyotype

   Diploid

   T(4;11)

   Misc

   IM/ND

11 (23)

5 (10)

24 (50)

8 (17)

CD22, (%)

96 [26-100]

CD20 ≥ 20%

10 (21)

Response

   CR

24 (52)

   CRp

8 (17)

   CRi

2 (4)

   ORR

34 (74)

   No response

5 (11)

   Early death

7 (15)

   Too early

2

Figure 1. Survival by salvage number

Disclosures: O'Brien: Pharmacyclics LLC, an AbbVie Company: Consultancy , Research Funding . Konopleva: Novartis: Research Funding ; AbbVie: Research Funding ; Stemline: Research Funding ; Calithera: Research Funding ; Threshold: Research Funding . Cortes: ARIAD Pharmaceuticals Inc.: Consultancy , Research Funding ; Teva: Consultancy , Research Funding ; Novartis: Consultancy , Research Funding ; BMS: Consultancy , Research Funding ; Pfizer: Consultancy , Research Funding .

*signifies non-member of ASH