Outcome of Patients with Relapsed/Refractory (R/R) Acute Lymphoid Leukemia (ALL) after Failure of Inotuzumab Ozogamicin

Background: Patients with relapsed/refractory (R/R) ALL have limited therapeutical options. Monoclonal antibodies have shown to be effective. Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 antibody conjugated to calicheamicin that has shown activity as a single agent in R/R ALL with 58% ORR in a phase II trial. More recently, a randomized phase III trial showed improvement of response rates of up to 80% compared to 30% for standard of care. Despite the high overall response rate to inotuzumab, responses are short-lived and most patients relapse.

Aim: The purpose of this study is to assess the outcome of patients with R/R ALL post inotuzumab ozogamicin failure.

Methods: We reviewed 151 patients with R/R ALL treated with inotuzumab ozogamicin as single agent (n=103) or part of a salvage regimen therapy (n=48) between 2009 and 2015. From this cohort of 151, we identified 67 (44%) patients with a median age of 47 years (4-84) who had either not responded to inotuzumab (n=42) or failed after a prior response of 2 months, range (<1 – 29) (n=25) and in whom a follow-up was available. These patients were evaluated for outcome analysis.

Results: Patient characteristics are listed in Table 1. The best prior response to inotuzumab included CR in 7 (10%) patients, CRp in 14 (21%), and CRi in 4 (6%). After a median follow-up of 19 months, (range, 1- 54) from inotuzumab failure, 6 patients (9%) remain alive. The median survival was 4 months, and the estimated 12-month survival rate was 13%. The median survival were 9 months, 3.5 months, and 3.4 months, respectively, for patients who received and failed inotuzumab as first salvage therapy, second salvage therapy, and third or more salvage therapy (P= 0.006). The estimated 12-month survival rates were 29%, 4%, and 10%, respectively. Patients with inotuzumab refractory disease had worse outcome post intozumab failure compared to those who responded and lost their response subsequently; the median overall survival post inotuzumab failure was 3 and 6 months (p=0.01), respectively . Among patients who relapsed, two received subsequent salvage therapy with blinatumomab. One of them responded and achieved a CR for 4 months. Four patients received an allogeneic stem cell transplantation; one of them remain alive at 55+ months. 

Conclusion: Outcome after inotuzumab failure is poor with a median survival of 4.4 months; these patients should be referred to clinical trials. Further use of inotuzumab ozogamicin earlier in the course of treatment may further improve the outcome.

 

Table 1 – Patient Characteristics
Characteristics	n = 67
	N	(%)
Median age, [range]	47 [4-84]
Age
< 40	29	(43)
40-60	16	(24)
>60	22	(33)
Sex
M	30	(45)
F	37	(55)
Performance Status
0-1	59	(88)
2	7	(10)
3	1	(1)
ALL sub-type
Pre-b ALL	65	(97)
biphenotypic	2	(3)
Cytogenetics
Ph+	11	(16)
t(4;11)	9	(13)
Complex	13	(19)
Diploid	8	(12)
Other	26	(39)
Hematological Parameters
Median WBC at start	4.1 [0.3-48.5]
Median WBC at Fail	2.3 [0-121.4]
Median PB, blasts at start	24.5 [0-93]
Median, PB, Blasts at fail	5.1 [0-96]
Median BM Blasts at start	75 [13-98]
Median BM Blasts at fail*	65 [0-99]
Timing of Inotuzumab after Relapse
as first salvage therapy	21	(31)
as second salvage therapy	27	(40)
as ≥ third salvage therapy	19	(28)
Number of Inotuzumab cycles
1 to 2 cycles	42	(63)
3 to 4 cycles	18	(27)
5 to 6 cycles	7	(10)
* Patients with 0 BM Blast had extramedullary disease