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1295 Phase II Study of the Frontline Hyper-CVAD in Combination with Ofatumumab for Adult Patients (pts) with CD-20 Positive Acute Lymphoblastic Leukemia (ALL)

Acute Lymphoblastic Leukemia: Clinical Studies
Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster I
Saturday, December 5, 2015, 5:30 PM-7:30 PM
Hall A, Level 2 (Orange County Convention Center)

Koji Sasaki, MD1, Paul B. Koller, MD2, Hagop M. Kantarjian, MD3, Deborah A Thomas, MD3, Maria R. Khouri4*, Guillermo Garcia-Manero, MD3, Rebecca Garris3*, Jorge E. Cortes, MD3, Heather Schroeder3*, Jad Chahoud, MD5, Tapan Kadia, MD3, Farhad Ravandi, MD3, Srdan Verstovsek, MD, PhD3, Naval Daver, MD3, Nitin Jain, MD3, Marina Konopleva, MD, PhD6, Susan O'Brien, MD3 and Elias Jabbour3

1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
2Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
5University of Texas Hosuton Health Science Center, Houston, TX
6Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: The hyper-CVAD regimen is an effective frontline regimen for de novo adult ALL. Expression of CD20 was identified as an adverse prognostic factor, associated with a higher incidence of relapse, lower 3-year complete remission duration (CRD) and lower 3-year overall survival (OS) rate. The addition of rituximab to the hyper-CVAD regimen in pts with CD20-positive ALL (≥20% expression by multicolor flow cytometry - FCI) improved outcome with 3-year CRD and OS rates by 68% and 65%, respectively. Ofatumumab (HuMax-CD20) targets a membrane proximal small-loop epitope on the CD20 molecule and was found to be more potent than rituximab in promoting complement-dependent cytotoxicity in vitro. Ofatumumab's safety and efficacy has been proven in chronic lymphocytic leukemia. Therefore a combination of the hyper-CVAD regimen and ofatumumab may be associated with better response rates, higher 3-year CRD and overall survival rates.

Methods: Pts with newly diagnosed ALL and pts who received one prior course of chemotherapy received 4 courses of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone; the odd courses 1, 3, 5, 7); ofatumumab was given on courses 1 and 3, and 4 courses of MTX-Ara-C (methotrexate-cytarabine; the even courses 2, 4, 6, 8); ofatumumab was given on courses 2 and 4. This treatment would be followed by POMP (6-mercaptopurine, MTX, VCR, prednisone) maintenance therapy for approximately 30 months, interrupted by intensifications months 6, 7 and 18, 19 with MTX/Pegylated asparaginase and hyper-CVAD-ofatumumab. Central nervous system prophylaxis with MTX and ara-C was administered. When indicated local radiotherapy was administered in patients with bulky mediastinal disease

Results: To date 37 pts with de novo ALL and 4 pts in complete remission (CR) previously treated (2 with prior cycle of hyper-CVAD, 1 post fludarabine-cytarabine based regimen, 1 with cyclophosphamide and dexamethasone) have received a median of 6 cycles (1-8) of therapy. Median age is 46 years (32–71). Median WBC at diagnosis was 5.4 x 109/L (1 -202 x 109/L). CD20 expression above 20% was found in 27 pts (66%), between 10 and 20% in 3 (7%) and below 10% in 11 (27%). 2 pts (5%) had concomitant CNS disease at diagnosis. Among the 34 pts with evaluable baseline cytogenetic analysis, 20 (49%) were abnormal. All but one pt (97%) achieved a CR after cycle 1 (4 pts were in CR at the start); 1 pt died of septic shock and multiple organ failure at day 21 of cycle 1. Thirty-eight (95%) pts achieved minimal residual disease (MRD) negativity as assessed by FCI; of whom 23 (64%) achieved MRD negativity after induction. Ten (27%) pts did not receive the full 8 planned courses of induction-consolidation; 16 (43%) pts are receiving maintenance in CR; 4 (11%) pts finished all treatment; 5 (%) pts were referred to allogeneic stem cell transplantation due to multiple cytogenetic abnormalities and delay in achieving negative MRD. Median time to neutrophil and platelet recovery for cycle 1 was 18 and 22 days after induction chemotherapy, respectively. Grade ≥ 3 toxicity included increase of LFT's in 13 pts (32%), increase of bilirubin in 7 (17%), nausea/vomiting in 4 (10%), mucositis in 3 (7%), neuropathy in 3 (7%), and thrombotic events in 1 (2%). Febrile neutropenia episodes during induction and consolidation cycles were reported at rates of 67% and 89%, respectively.  With a median follow up of 15 months (1-45), 35 pts are alive; 6 pts relapsed and one had molecular relapse only. Six pts died: 1 at C1D22 of sepsis and intracranial bleed; 1 at C3D17 of sepsis and multiple organ failure; 1 at maintenance C16D35 of sepsis; 1 of relapse post ASCT; 1 post salvage therapy for minimal residual disease relapse; 1 of progressive disease after relapse. The 2-year PFS and OS rates were 68% and 87% respectively.

Conclusion: The combination of hyper-CVAD with ofatumumab is safe and highly effective in pts with CD20-positive ALL.

Table 1. Patient characteristics and outcome

 

N (%)/ Median [range]

N=41

Age (yrs)

44 [22-71]

Sex

Male

25 (61)

Female

16 (39)

PS

0-1

38 (93)

2-3

3 (7)

WBC (x 109/L)

5.4 [0.7-201.7]

CNS disease positivity

2 (5)

CD20 + (%)

1-10

9 (22)

10-20

3 (7)

>20

27 (66)

Pos

2 (5)

CG

Diploid

14 (34)

Abnormal

20 (49)

IM/ND

7 (17)

Response

CR

37/38 (97)

 

CR after induction

37/38 (97)

 

MRD at CR

23/36 (64)

 

MRD overall

38/40 (95)

 

Early death

1 (3)

Figure 1. Progression-free survival and overall survival

 

Disclosures: Cortes: Teva: Research Funding ; BerGenBio AS: Research Funding ; Pfizer: Consultancy , Research Funding ; Novartis: Consultancy , Research Funding ; Ariad: Consultancy , Research Funding ; BMS: Consultancy , Research Funding ; Astellas: Consultancy , Research Funding ; Ambit: Consultancy , Research Funding ; Arog: Research Funding ; Celator: Research Funding ; Jenssen: Consultancy . Chahoud: American Society of Hematology (ASH): Other: 2015 HONORS Award recipient . Verstovsek: Incyte Corporation: Research Funding . Konopleva: Novartis: Research Funding ; AbbVie: Research Funding ; Stemline: Research Funding ; Calithera: Research Funding ; Threshold: Research Funding . O'Brien: Pharmacyclics LLC, an AbbVie Company: Consultancy , Research Funding .

*signifies non-member of ASH