Acute Lymphoblastic Leukemia ⎼ Posters and Abstracts from San Diego 60th ASH Annual Meeting & Exposition

Blinatumomab for Minimal Residual Disease in Adults with B-Cell Precursor Acute Lymphoblastic Leukemia BLAST Study Follow-Up Gökbuget N, et al. ASH 2018. Abstr 554.

BLAST Study Design1 and Follow-Up2 Open-label, single-arm phase 2 study Pts (N=116, age ≥18 years with BCP-ALL in first or later hematologic CR and with persistent or recurrent MRD≥10-3 after a minimum of 3 cycles of intensive chemotherapy) received blinatumomab 15 μg/m2/d by continuous IV infusion for up to 4 cycles (each cycle: 4 weeks of blinatumomab infusion → 2 weeks, treatment-free). MRD evaluation: real-time qPCR performed mostly in the central reference laboratory or in national reference laboratories. The primary endpoint: the rate of complete MRD response after blinatumomab cycle 1 The current update (minimum F/U = 3 years; median F/U = 53.1 months after blinatumomab treatment) reports long-term OS in 110 pts with Ph- BCP-ALL and <5% blasts at enrollment, including 74 who received allo-SCT while in continuous CR after blinatumomab treatment. 1. Gökbuget N, et al. Blood. 2018;131:1522-1531. 2. Gökbuget N, et al. ASH 2018. Abstr 554.

BLAST Study Follow-Up Overall Survival Median OS = 36.5 months (reached a plateau) Complete MRD responders (n=85) = NR (95% CI: 27.3 months to NR) Underwent allo-SCT in continuous CR (n=61) = NR (95% CI: 25.7 months to NR) MRD+ in CR1 (n=60) = NR (95% CI: 29.5 months to NR) MRD non-responders (n=22) = 12.5 months (95% CI: 3.2 to 39.7) Underwent allo-SCT in continuous CR (n=10) = 16.1 months (95% CI: (1.1 to NR) MRD+ in CR1 (n=13) = 10.6 months (95% CI: 2.7 to 39.7) Gökbuget N, et al. ASH 2018. Abstr 554.

BLAST Study Follow-Up Summary and Faculty Takeaways This update further demonstrates the long-term OS benefits of blinatumomab treatment in adults with MRD+ BCP-ALL. The MRD+ is a sign of disease refractoriness, not just a biomarker, and pts who are MRD+ have a very poor outcome. We should not transplant pts while they are MRD+, we should make every effort to attain MRD- status, and blinatumomab is highly effective in this regard. In practice, check for MRD+, whether due to a persistent disease or relapse, give them blinatumomab and, then, if MRD-, go for transplant. Down the road, the role of transplant may become questionable; do we go for transplant or not? I would say, today, yes, but in the future, things may change. Gökbuget N, et al. ASH 2018. Abstr 554.

Inotuzumab Ozogamicin + Mini-Hyper-CVD ± Blinatumomab in Newly Diagnosed Older Patients With Ph- ALL Phase II Study Short NJ, et al. ASH 2018. Abstr 36.

INO + Mini-Hyper-CVD ± Blinatumomab Phase II Study Design Pts (N=58), median age 68 years (required to have a PS of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl), with newly diagnosed Ph- pre-B ALL received mini-hyper-CVD for up to 8 cycles. INO given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1, and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Pts 1-6 received 1.3 mg/m2 for cycle 1 followed by 0.8 mg/m2 for subsequent cycles, while pts 7+ received the phase II dose of 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. Short NJ, et al. ASH 2018. Abstr 36.

INO + Mini-Hyper-CVD ± Blinatumomab Phase II Study Protocol Amendment After the observation of VOD, the protocol was amended in 9/2015 to use lower doses of INO. Pts (35+) received INO at 1.3 mg/m2 in cycle 1, and 1 mg/m2 in all of the subsequent cycles. Another amendment was made in 3/2017 (pts 50+) to give INO in split doses each cycle (0.6 mg/m2 on day 2, and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2, and 8 of cycles 2-4) and 4 cycles of blinatumomab at standard dosing after the INO-based cycles, for a total of 4 cycles, and before the initiation of the maintenance therapy (i.e. cycles 5-8). Short NJ, et al. ASH 2018. Abstr 36.

INO + Mini-Hyper-CVD ± Blinatumomab Key Findings ORR = 98% (CR = 87%) 3-year OS = 54% MRD- status by 6-color flow cytometry was achieved in 39/52 pts (75%) after 1 cycle and 54/57 pts (95%) overall. There were no early deaths, and the 30-day and 60-day mortality rates were 0% and 3%, respectively. 54% of pts remain on treatment. Short NJ, et al. ASH 2018. Abstr 36.

INO + Mini-Hyper-CVD ± Blinatumomab Summary and Faculty Takeaways Mini-hyper-CVD + INO ± blinatumomab proved to be safe and effective in elderly pts with newly diagnosed Ph- ALL. Compared to a similar historical cohort of older pts treated with hyper-CVAD ± rituximab, mini-hyper-CVD + INO ± blinatumomab resulted in significantly higher 3-year OS. This regimen is likely to set the stage for a new standard of care for elderly pts with newly diagnosed Ph- ALL. Short NJ, et al. ASH 2018. Abstr 36.

Sequential Mini-Hyper-CVD + Inotuzumab Ozogamicin ± Blinatumomab in Patients With R/R Ph- ALL Phase II Study Sasaki K, et al. ASH 2018. Abstr 553.

Mini-Hyper-CVD + INO ± Blinatumomab Phase II Study Design The mini-hyper-CVD (cycles 1, 3, 5, 7) included cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg on days 1 and 8), and dexamethasone (20 mg on days 1-4 and 11-14) without doxorubicin; cycles 2, 4, 6, 8 included methotrexate (250 mg/m2 on day 1) and cytarabine (0.5 g/m2 given every 12 h on days 2 and 3). INO was originally given on day 3 of the first 4 cycles at the dose of 1.3-1.8 mg/m2 at cycle 1, followed by 1.0-1.3 mg/m2 in subsequent cycles. Rituximab and IT chemotherapy were given for first 4 courses. Sasaki K, et al. ASH 2018. Abstr 553.

Mini-Hyper-CVD + INO ± Blinatumomab Phase II Study Protocol Amendment After 67 pts were treated protocol was amended to incorporate 4 cycles of blinatumomab after 4 cycles of mini-hyper-CVD + INO, which was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m2 in cycle 1, respectively, and on days 2 and 8 of subsequent cycles at the dose of 0.3 mg/m2. Blinatumomab was infused over 28 days every 42-day cycle for 4 cycles. Sasaki K, et al. ASH 2018. Abstr 553.

Mini-Hyper-CVD + INO ± Blinatumomab Key Findings From 2/2013 to 5/2018, 84 pts (median age = 35 years; 23% of pts had prior allo-SCT) were enrolled and treated, including 17 pts with mini-hyper-CVD + INO + blinatumomab. The median follow-up was 31 months. ORR = 80% (CR = 58%) Median OS = 25, 6, and 7 months in salvage 1, 2, and 3 or more, respectively MRD- status by 6-color flow cytometry was achieved in 51/64 pts (80%); 85% in salvage 1. The VOD incidence was reduced from 9/61 (15%) with single dose of INO to 0/18 (0%) with weekly divided dose schedule. Sasaki K, et al. ASH 2018. Abstr 553.

Mini-Hyper-CVD + INO ± Blinatumomab Summary and Faculty Takeaways The combination of mini-hyper-CVD and INO ± blinatumomab is effective and shows encouraging results in patients with R/R Ph- ALL. Historical comparison showed median OS of 14 months and 6 months in hyper-CVD + INO ± blinatumomab and INO as a single agent, respectively. The VOD risk can be reduced with fractionated INO dosing. This represents a new standard of care for pts with R/R Ph- ALL. Sasaki K, et al. ASH 2018. Abstr 553.

Sequential Hyper-CVAD With Blinatumomab as Frontline Therapy for Adults With Ph- B-Cell ALL Phase II Study Richard-Carpentier G, et al. ASH 2018. Abstr 32.

Sequential Hyper-CVD + Blinatumomab Phase II Study Design Pts (N=19; median age 42 years) had newly diagnosed untreated (or were in CR after one prior course of hyper-CVAD; n=3) Ph- B-ALL or B-cell lymphoblastic lymphoma, ECOG PS of 0-3, with normal liver, kidney, and cardiac function. Therapeutic regimen: 4 alternating cycles of Hyper-CVAD → 4 consecutive cycles of blinatumomab (4 weeks every 6 week-cycle) All pts received 8 prophylactic IT injections with methotrexate and cytarabine during the first 4 cycles of treatment. Pts with CD20+ ALL (≥1% cells) received a total of 8 doses of rituximab (375 mg/m2) or ofatumumab (2000 mg) during the hyper-CVAD cycles. Maintenance: POMP (cycles 1-3, 5-7, 9-11 and 13-15) alternating with blinatumomab (cycles 4, 8 and 12) Richard-Carpentier G, et al. ASH 2018. Abstr 32.

Sequential Hyper-CVD + Blinatumomab Key Findings ORR = 100% (CR = 100%) 1-year OS = 93% MRD- status by 6-color flow cytometry was achieved in 93% of the pts after 1 cycle of therapy. The treatment was well tolerated. One patient developed transient Grade 3 CRS and 1 had Grade 3 ataxia; both recovered after holding blinatumomab therapy and dexamethasone administration; thereafter, treatment was resumed with no AE recurrence. With a median follow up of 17 months, 18 pts (95%) are alive. Richard-Carpentier G, et al. ASH 2018. Abstr 32.

Sequential Hyper-CVD + Blinatumomab Summary and Faculty Takeaways The sequential combination of Hyper-CVAD and blinatumomab in newly diagnosed adult patients with B-ALL is safe and highly effective. Of note, most of the pts had bad features such as t(4;11), CRLF2+, TP53 mutations, and others. This study is still accruing pts. Eventual positive outcomes may mean that in the future we can get rid of the intensive chemotherapy. Richard-Carpentier G, et al. ASH 2018. Abstr 32.

Blinatumomab Followed by POMP Maintenance in Older Patients With Newly Diagnosed Ph- B-Cell ALL Phase II SWOG 1318 Trial Advani AS, et al. ASH 2018. Abstr 33.

Blinatumomab → POMP Maintenance Phase II SWOG 1318 Trial Design Pts (N=29; median age 75 years) received blinatumomab for induction (standard dose for 1-2 cycles) until CR/CRi → 3 cycles of blinatumomab post-remission therapy → 18 months of maintenance POMP. A total of 8 doses of IT methotrexate were administered as CNS prophylaxis. Response was assessed at the completion of 1-2 cycles of blinatumomab. The primary objective of the study was to estimate 3-year OS. Advani AS, et al. ASH 2018. Abstr 33.

Phase II SWOG 1318 Trial Key Findings ORR = 66% (CR = 100%) 1-year OS = 67% 1-year DFS = 58% MRD- status by 8-color flow cytometry was achieved in 92% of the pts after 1 cycle of therapy. The treatment was well tolerated. Grade 3 CRS (n=1) and Grade 3 neurotoxicity (n=1) were reported. Advani AS, et al. ASH 2018. Abstr 33.

Phase II SWOG 1318 Trial Summary and Faculty Takeaways Blinatumomab was well tolerated and effective in the treatment of newly diagnosed elderly patients with Ph- B-cell ALL. Further follow-up will ascertain the durability of these responses. Advani AS, et al. ASH 2018. Abstr 33.

Subgroup Analysis of HRQoL Blinatumomab vs SOC Chemotherapy in Patients With R/R Ph- ALL TOWER Trial Stein AS , et al. ASH 2018. Abstr 3967.

Adults with heavily pre-treated Ph- BCP-ALL TOWER Trial Design Blinatumomab (n=271) Induction, if ≤5% bone marrow blasts → consolidation Week 1: 9 μg/d; weeks 2-4: 28 μg/d; weeks 5 & 6: no therapy If ≤5% bone marrow blasts → maintenance Four-week continuous infusion every 12 weeks Adults with heavily pre-treated Ph- BCP-ALL (N=405) Randomization 2 : 1 (blinatumomab : SOC) SOC Chemotherapy (n=134) Induction, if ≤5% bone marrow blasts → consolidation If ≤5% bone marrow blasts → maintenance The primary endpoint: OS Secondary end points: CR, CR duration, EFS, MRD, AEs Chemotherapy: fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor +/- anthracycline; high-dose cytarabine-based regimen; a high-dose methotrexate-based regimen; clofarabine-based regimen. Kantarjian H, et al. N Engl J Med. 2017;376:836-847.

TOWER Trial: HRQoL Subgroup Analysis Key Findings HRQoL was assessed using the EORTC QLQ-C30 Questionnaire on days 1 (baseline), 8, and 15; on day 29 of cycle 1; days 1, 15, and 29 of consolidation; and at the safety follow-up. The questionnaire included 1 global health status scale, 5 functioning scales, 3 symptom scales, and 6 single-symptom items. In total, 342 pts (blinatumomab, n=247; SOC, n=95) had ≥1 HRQoL result: low blasts, n=87 (blinatumomab, n=64; SOC, n=23); high blasts, n=255 (blinatumomab, n=183; SOC, n=72) Global health status was improved by blinatumomab regardless of baseline blast level; however, this improvement was somewhat greater in the low blasts group. When the function scores worsened, the extent of worsening was almost always smaller for blinatumomab vs SOC, particularly in the high blasts group. Functioning status scores tended to stay the same or worsen with both blinatumomab and SOC regardless of blast level, except emotional scores, which improved with blinatumomab regardless of blast level. Generally, symptom scores improved with blinatumomab but not with SOC, particularly in patients with high blasts. Stein AS , et al. ASH 2018. Abstr 3967.

TOWER Trial: HRQoL Subgroup Analysis Summary and Faculty Takeaways Blinatumomab improved HRQoL in pts with R/R Ph- BCP-ALL and delayed the time to clinically meaningful deterioration in HRQoL vs SOC. The difference between blinatumomab and SOC with regard to HRQoL was greater among pts with high disease burden. Of note, blinatumomab does improve the functioning of the pts, not only their survival and their response rates. Stein AS , et al. ASH 2018. Abstr 3967.

Abbreviations (1 of 2) AEs: adverse events ALL: acute lymphoblastic leukemia allo-SCT: allogeneic stem-cell transplantation AST/ALT: aspartate transaminase/alanine transaminase BCP: B-cell precursor CR: complete remission CRi: CR with incomplete count recovery CRS: cytokine release syndrome DFS: disease-free survival ECOG PS: Eastern Cooperative Oncology Group Performance Status EFS: event-free survival F/U: follow-up HRQoL: health-related quality of life Hyper-CVAD: hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate/cytarabine every 21 days INO: inotuzumab ozogamicin

Abbreviations (2 of 2) IT: intrathecal IV: intravenous MRD: minimal/measurable residual disease Mini-hyper-CVD: cyclophosphamide and dexamethasone at 50% dose reduction, no doxorubicin, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m2 × 4 doses NR: not reached ORR: overall response rate OS: overall survival Ph: Philadelphia chromosome POMP: 6‐mercaptopurine, vincristine, methotrexate, and prednisone qPCR: quantitative polymerase chain reaction R/R: relapsed/refractory SOC: standard of care TKI: tyrosine kinase inhibitor ULN: upper limit of normal VOD: veno-occlusive disease