Updated clinical and biological information from the two-stage phase II study of imatinib mesylate in subjects with relapsed/refractory neuroblastoma

Figures & data

Table 1. Clinical update on the fourteen subjects enrolled in the trial that did not progress during the first two cycle of Imatinib mesylate.

Enrollment number	Status pre Imatinib	Disease status pre Imatinib (PT, B-BM, ^123mIBG) *	Imatinib cycles	Best response	Time to progression from last Imatinib (months)	Rescue Therapy°	State at follow-up (2017)
22	PR after 1° line therapy	PT, B-BM, multiple	14	PR	1	VP16	Dead
9	PR after 1° line therapy	BM, one	12	CR	1	VP16	Dead
10	PR after 1° line therapy	PT, multiple	8	SD	-	none	Dead ^(a)
8	PR after 2° line therapy	PT, B-BM, multiple	29	PR	1	VP16	Dead
12	PR after 2° line therapy	PT, B, multiple	4	SD	4	none	Dead
13	PR after 2° line therapy	PT, BM, multiple	12	CR	3	TVD	Alive
15	PR after 2° line therapy	PT, BM, multiple	12	CR	1	TEMIRI	Dead
11	PR after 2° line therapy	B/BM, two	2	SD	1	VP16	Dead ^(b)
7	PR after 2° line therapy	B, multiple	3	SD	1	none	Dead
14	PR after 2° line therapy	B, one	4	SD	1	VP16	Dead
20	Resistant relapse	PT, tumor	4	SD	12	VP16	Dead
17	Resistant relapse	BM, one	6	CR	1	VP16	Dead
4	Untreated relapse	PT, B-BM, multiple	12	CR	–	none	Alive
6	Untreated relapse	PT, tumor	6	SD	4	surgery	Alive

Patients highlighted in blue were alive at the time of the first report of the trial ⁴.

* PT = presence of primary tumor, B = presence of bone metastasis, BM = presence of bone marrow metastasis, number of ¹²³mIBG spots.

° VP16 = oral etoposide, TVD = Topotecan/Vincristine/Doxorubicine, TEMIRI = temozolomide-irinotecan

^(a) This patient died of myelodisplastic syndrome with evolution to acute leukemia; ^(b) This patient died of a second malignancy (leukemia).

Figure 1. Kaplan-Meier plot of overall and progression-free survival after the first imatinib mesylate of the 24 subjects with relapsed/refractory NB enrolled in the EudraCT: 2005–005778-63 trial.

Figure 2. Association between imatinib mesylate exposure and response/outcome. A) Chart of steady state $AU{C}_0^{\mathrm{\infty }}$ at first cycle of treatment versus response score (CR = 3, PR = 2, SD = 1 and PD = 0). B) Chart of steady state $AU{C}_0^{\mathrm{\infty }}$ at second cycle of treatment versus response score. Each subject is indicated by the same symbol in the two graphs. C) Box-plot of $AU{C}_0^{\mathrm{\infty }}$ at first cycle in responsive (CR+PR, blue), SD (yellow) and PD (red) subjects. D) Box-plot of $AU{C}_0^{\mathrm{\infty }}$ at second cycle in responsive (CR+PR, blue), SD (yellow) and PD (red) subjects. E) Box-plot of $AU{C}_0^{\mathrm{\infty }}$ at first cycle in subjects alive (blue) and dead (red) at 24 months after first Imatinib mesylate. F) Box-plot of $AU{C}_0^{\mathrm{\infty }}$ at second cycle in subjects alive (blue) and dead (red) at 24 months after first imatinib mesylate.

Figure 3. Plasma levels of IFN-γ (A), TNF-α (B), TGF-β (C), IL-10 (D), CXCL12 (E) and sB7-H6 (F) measured in 13 subjects, at study entry (basal) and after 1 or 2 cycles of imatinib mesylate. Each subject is indicated by the same symbol in all graphs.

Figure 4. Expression levels (Log 2^{-delta Cq}) of NKp30 receptor mRNA isoform A (A, B), isoform B (C, D) and isoform C (E, F) evaluated in PB samples (A, C, E) and BM samples (B, D, F), at study entry (basal) and after 2 cycles of Imatinib mesylate in 7 subjects. Each subject is indicated by the same symbol in all graphs.

Figure 5. Box-plot of NKp30 ∆AB (A, B), ∆AC (C, D) and ∆BC (E, F), evaluated in PB samples (A, C, E) and BM samples (B, D, F) in responsive (CR+ PR, response, blue) and no responsive (SD + PD, progression, red) subjects, using data measured after 2 cycles of Imatinib mesylate. ∆ was calculated according to the formula ∆NKp30_x NKp30_y = CqNKp30_{y –} CqNKp30_x.