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83 Frontline Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) for Older Patients with Acute Lymphoblastic Leukemia (ALL)Clinically Relevant Abstract

Acute Lymphoblastic Leukemia: Clinical Studies
Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies I
Saturday, December 5, 2015: 1:00 PM
W230, Level 2 (Orange County Convention Center)

Elias Jabbour1, Susan O'Brien, MD1, Koji Sasaki, MD2, Deborah A Thomas, MD1, Guillermo Garcia-Manero, MD1, Farhad Ravandi, MD1, Gautam Borthakur, MD1, Nitin Jain, MD1, Marina Konopleva, MD, PhD1, Jovitta Jacob, RN1*, Rebecca Garris1*, Jorge E. Cortes1 and Hagop M. Kantarjian, MD1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Elderly patients with ALL have a significantly poor outcome. This is primarily due to poor tolerance of intensive chemotherapy. Addition of targeted non-myelosuppressive therapy to effective low-intensity chemotherapy might improve outcome. CD22 expression occurs in >90% of patients with ALL. Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in relapsed/refractory ALL (Kantarjian et al. Lancet Oncology 2012).

Methods: Patients ≥60 years with newly-diagnosed B-cell ALL were eligible for the chemotherapy with 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) in combination with IO given on Day 3 of each of the first 4 courses. Rituximab and intrathecal chemotherapy were given for first 4 courses. The first 6 pts received 1.3 mg/m2 for cycle 1 followed by 0.8 mg/m2 for subsequent cycles; Pts 7 onwards received 1.8 mg/m2 for Cycle 1 followed by 1.3 mg/m2 for subsequent cycles.

Results: Thirty-four patients (21 men, 13 women) have been treated so far. Patient characteristics and outcome are summarized in Table 1.  Median age is 69 years (range 60-79). Median follow-up is 19 months. Of the 31 patients evaluable for response (3 started in CR), 30 (97%) achieved CR/CRp (25 CR, 5 CRp). All patients achieving CR have also achieved flow-cytometry MRD negative status, in 80% at the time of CR achievement. Median time to platelet and neutrophil recovery was 23 days (18-91), and 16 days (12-49) after induction, and was 22 days (14-64), and 17 days (13-49) after subsequent cycles. Grade 3-4 toxicities ≥10% included prolonged thrombocytopenia (n=27; 79%), infections during consolidation (n=25; 73%), infections during induction (n=18; 52%), hyperglycemia (n=17; 50%), hypokalemia (n=12; 35%), hyperbilirubinemia (n=8; 24%), increased ALT/AST (n=7; 21%), and hemorrhage (n=6; 18%). Of note, veno-occlusive disease (VOD) was observed in 4 patients (11%); 1 in CR and negative MRD, G2 VOD at C3D57; 1 in CR and negative MRD, G5 VOD at C2D40; 1 in CR and negative MRD, G2 VOD at D43 post matched related allogeneic stem cell transplantation with conditioning of fludarabine and busulfan after 4 cycles of mini-hyper-CVD + IO; and 1 in CR and negative MRD, G2 VOD at C2D70. At the last follow-up, 23 (68%) are alive and 22 (65%) in CR. Eleven patients (32%) died: 1 had primary refractory ALL and died after the first salvage; 2 relapsed after receiving 2 and 3 courses only due to prolonged myelossuppression and died of disease progression; and 8 died in CR from sepsis (n=4), gunshot wound (n=1), VOD (n=1), dementia (n=1), and unknown cause (n=1). Two patients (6%) received allogeneic stem cell transplantation. Four patients (12%) are currently receiving consolidation chemotherapy with a median of 5 cycles (1-8); 16 patients (47%) are receiving POMP maintenance chemotherapy. The 2-year progression-free survival and overall survival rates were 87% and 70%, respectively. The mini-hyper-CVD (n=34) appears superior to the historical HCVAD +/- rituximab (n=46) in similar patient population (2-year OS, 70% and 38%, respectively; Figure 1).

Conclusions: The combination of IO with low-intensity mini-hyper-CVD chemotherapy is safe and shows encouraging results (97% CR/CRp) in the frontline setting in older patients with ALL. These results appear to be better than those achieved with a chemotherapy alone only approach and may become the new standard of care for frontline treatment of older patients with ALL.

Table 1. Patient characteristics and outcome

Characteristic

Median (range) / No. (%)

N=34

Age (yrs)

69 [60-79]

Male

21 (62)

Performance Status (ECOG) ≥ 2

4 (12)

WBC at DX

3.5 [0.6-111.0]

WBC at DX ≥ 50

2 (6)

Karyotype

   Diploid

   Complex

   Misc

   IM

11 (32)

15 (44)

5 (15)

3 (9)

CD22 Positivity

97 [72-100]

CD20 ≥ 20

20 (65)

Response

   CR

25/31 (81)

   CRp

5/31 (31)

      Cytogenetic CR

19/19 (100)

      Negative MRD, D21

20/25 (80)

      Negative MRD, Overall

33/33 (100)

   ORR

30/31 (97)

   No response

1/31 (3)

   Early death

0

Figure 1. Survival with mini-hyper-CVD+IO vs hyper-CVAD +/- rituximab in frontline ALL

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: Teva: Consultancy , Research Funding ; Pfizer: Consultancy , Research Funding ; Novartis: Consultancy , Research Funding ; BMS: Consultancy , Research Funding ; ARIAD Pharmaceuticals Inc.: Consultancy , Research Funding .

*signifies non-member of ASH