Page 158 - Haematologica May 2022

J.N. Gustine et al.
days (95% CI: 13-27); treatment was started within 4 and 8 weeks of T0 for 69% and 93% of patients, respectively (Figure 2B). Reasons for not receiving salvage therapy included patient choice of hospice care (n=2) and decom- pensated heart failure from cardiac AL amyloidosis (n=1). The ORR and MRR to the first salvage regimen following T0 were 56% (27/48) and 44% (21/48), respectively. Among patients who responded to salvage therapy, the median DOR was 48 months (34 months-NR), and the 3-year DOR was 61% (41-90%). Twenty patients were refractory (42%) to the first salvage regimen; 11 patients received subsequent treatment, and nine patients died from progressive disease before receiving additional treat- ment. The specific treatment regimens utilized for the first salvage regimen after T0 with the corresponding response rates and DOR are detailed in Table 3.
We then performed additional analyses to identify fac- tors at T0 predictive of a response to the first salvage regi- men. Patients with quadruple-class (rituximab, protea- some inhibitor, alkylator, ibrutinib) exposed disease had significantly lower odds of a response to the first salvage regimen compared to those without (33% vs. 73%; OR 0.18, 95% CI: 0.04-0.76; P=0.01). Age, time on ibrutinib, time from WM diagnosis, sex, hemoglobin level, platelet count, serum IgM level, number of previous therapies, and MYD88 and CXCR4 mutation status were not associated with higher or lower odds of a response to the first salvage regimen following T0 (P>0.05 for all comparisons; Online Supplementary Table S2).
The timing of salvage therapy following T0 also impact- ed the likelihood of a response to the first salvage regimen. Patients who received salvage therapy ≤7 versus >7 days from T0 had significantly higher odds of a response (75% vs. 45%; OR 4.47, 95% CI: 1.07-23.2; P=0.03). Bridging ibrutinib with salvage therapy was also associated with a significantly higher response rate (100% vs. 49%; P=0.01). There was a trend for a higher response rate with ibrutinib bridging versus initiating salvage therapy within 7 days of T0 (100% vs. 58%; P=0.054).
In a multivariate model, we evaluated quadruple-class exposed disease against receiving salvage therapy ≤7 days after T0 for the odds of a response to salvage therapy. Both quadruple-class exposed disease (OR 0.20, 95% CI: 0.05- 0.73; P=0.02) and receiving salvage therapy ≤7 days after T0 (OR 4.12, 95% CI: 1.07-18.9; P=0.048) remained inde-
pendently associated with the odds of attaining a response to salvage therapy.
Eight patients bridged ibrutinib with the subsequent treatment. Ibrutinib overlapped with the salvage regimen for two cycles in six patients, and one cycle in two patients. The following treatment regimens were added while continuing ibrutinib: bendamustine and rituximab (Benda-R; n=3), bortezomib, dexamethasone, and ritux- imab (BDR; n=3), ixazomib, dexamethasone, and ritux- imab (IDR; n=1), and fludarabine and rituximab (Flu-R; n=1). The ORR and MRR to bridging ibrutinib with sal- vage therapy were both 100%. Six patients were evalu- able for an IgM rebound; two patients had developed symptomatic hyperviscosity as part of clinical progression on ibrutinib and were deemed unevaluable for an IgM rebound. Only one patient (17%) had an asymptomatic IgM rebound after bridging ibrutinib with Benda-R for two cycles, which subsequently resolved with two addi- tional treatment cycles. The two non-evaluable patients with symptomatic hyperviscosity were able to stop plasmapheresis after one cycle of bridging with BDR, and then discontinued ibrutinib without evidence of an IgM rebound following one additional cycle of bridging. Ibrutinib was bridged with Flu-R in one patient with Bing- Neel syndrome, and there was no evidence of an IgM rebound or worsening of neurological symptoms follow-
Figure 1. Peak absolute change in serum immunoglobulin M level following discontinuation of ibrutinib. Values are depicted for each of the 48 patients who were evaluable for an immunoglobulin M (IgM) rebound.
Table 3. Response outcomes according to each salvage regimen utilized following ibrutinib discontinuation.
Salvage Regimen N
Benda-R 22 PI-Dex-R 8 Flu-R 4 CCD 2 R-CHOP 2 Ofatumumab 1 Daratumumab 2 Ibrutinib+PI 1 Everolimus 1
≥Minor Response (ORR)
14 (64) 5 (63) 4 (100)
≥Partial Response (MRR)
11 (50) 4 (50) 3 (75)
DOR (months)
3-yr: 57% 3-yr: 80% 3-yr: 67%
1(50) 1(50) 2.7+ 1 (50) 1 (50) 26+
1 (100) 0 (0) 15
0(0) 0(0) -
0(0) 0(0) -
0(0) 0(0) -
A total of 48 of 51 patients (94%) received at least one salvage therapy following time-zero (T0). Five patients received investigational agents and the responses are not included in the table.One patient with AL amyloidosis received consolidation with an autologous stem cell transplant following Benda-R.The following proteasome inhibitors were used as part of a PI-Dex-R regimen: bortezomib (n=5); carfilzomib (n=2); ixazomib (n=1). ORR: overall response rate; MRR: major response rate; DOR: duration of response; yr: years; PI-Dex-R: proteasome inhibitor, dexamethasone, rituximab; Flu-R: fludarabine, rituximab; CCD: carfilzomib, cyclophosphamide, dexamethasone; R-CHOP: rituximab, cyclophos- phamide, doxorubicin, vincristine, prednisone.
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