Outcome of Adult Patients with Philadelphia Negative B Cell Acute Lymphoblastic Leukemia after Frontline Therapy Failure

Introduction: Intensive induction-consolidation chemotherapy achieves high rates of complete response (CR) in 90% of patients with newly diagnosed acute lymphoblastic leukemia (ALL). However, almost a half of the patients relapse and their outcome after frontline chemotherapy failure is essentially poor.

Methods: We retrospectively reviewed 463 patients with newly diagnosed Philadelphia-negative ALL from June 2002 to February 2015 at our institution. Overall survival was defined as the time interval from the date of relapse to the date of death. Kaplan-Meier method was used for survival analysis.

Results: Of the 463 patients, 155 (33%) relapsed. Data on salvage therapy and long term follow-up was available in 76 patients (17%). The median time to relapse was 15 months (range, 1-111 months). The median number of salvage regimens administered was 1 (range, 1-7). Overall, 76 patients received at least 1 salvage therapy. Thirty (39%) patients received at least 2 salvage regimens and 18 (24%) received 3 or more salvage regimens. Baseline patient characteristics are summarized in the table 1. Median follow-up after frontline therapy failure was 16 months. The median survival after relapse was 8.3 months with the 1- year and 2-year survival rates being 46 % and 28% respectively.

Salvage 1 included augmented HCVAD [n=13; 7/13 responses (6 CR, 1 CRp) for a median of 6 months], asparaginase based therapies [n=6; 2/6 response (2 CR) for a median of 2 months], monoclonal antibodies (MAB), blinatumomab, inotuzumab ozogamicin  [n=19; 11/19 responses (6 CR, 5 CRp) for a median of 7 months], HCVAD + anti-CD20 antibody [n=11; 8/11 responses (5 CR, 3 CRp) for a median of 6 months], Miscellaneous [n=22; 2/22 responses (2 CR)] and HCVAD [n=5; 1/5 response (1 CR) for 1 month]. The overall response rate to Salvage 1 was 41% (22 CR, 9 CRp) for a median of 6 months. Nineteen (25%) patients received subsequent allogeneic stem cell transplantation (ASCT); 11 of them are alive with a median of 2 years with 7 of them in CR.

Thirty patients received a second salvage regimen; the most commonly used one consisted of MAB (blinatumomab; inotuzumomab ozogamicin) [n=8; 4/8 responses (2 CR, 2 CRp) for a median of 2.5 months]. The overall response rate to salvage 2 was 30% (6 CR, 3 CRp) for a median of 3 months.

At the last follow-up, overall 23 patients remained alive, 9 of them in CR.

Conclusions: Outcome of patients with Philadelphia-negative ALL post frontline therapies failure is poor with a median survival of only 8.3 months. Though some salvage therapies can induce remissions, response durations are limited. Stem cell transplant after remission offers a potential of long term cure. These patients should be referred to clinical trials.

Table 1. Baseline characteristics and outcome of adults with relapsed B cell ALL (Ph -)

who received salvage chemotherapy :

	N (%)/ Median [range] N= 76
Age (years)	36 (18-86)
Age ³ 60	15 (20)
Male	46 (61)
PS 2-3	9 (12)
WBC at diagnosis (x 109/L)	7.2 [1-602]
CD20 positivity at diagnosis	24 (32)
Cytogenetic Abnormality
Diploid	22 (29)
Hypodiploid	8 (11)
Hyperdiploid	12 (16)
t(4;11)	5 (7)
Miscellaneous	28 (37)
Type of Induction chemotherapy, No. (%)
Augmented BFM	28 (37)
HCVAD	21 (28)
HCVAD + anti-CD20 antibody	27 (35)
Overall response to frontline therapy
CR	73 (96)
CR without platelet count recovery	2 (3)
Partial response	1 (1)
Median response duration, (month)	15[1-63]
Response duration <12 months	35 (46)
Complete response to salvage chemotherapy
S1	31/76 (41)
S2	9/30 (30)
S3 or more	3/18 (17)
Allogeneic stem cell transplant	19 (25)

                Figure 1. Overall survival