To complement The ASCO Post’s continued comprehensive coverage of the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel therapies for newly diagnosed and relapsed or refractory acute lymphoblastic leukemia (ALL). For full details of these study abstracts, visit ashpublications.org.
GUEST EDITORS
Syed Ali Abutalib, MD
Daniel J. DeAngelo, MD, PhD
Newly Diagnosed ALL
ABSTRACT 740: Updated results of GIMEMA LAL2116 D-Alba study: Front-line dasatinib plus steroids as induction therapy followed by blinatumomab, in adults with BCR-ABL1–positive ALL (n = 63)1
Methods: The primary objective of the trial is to evaluate the activity of a combination approach based on dasatinib and blinatumomab in obtaining minimal residual disease (MRD) negativity (complete molecular response, eg, BCR-ABL1/ABL1 = 0) or positive nonquantifiable disease.
Results: The median follow-up was 10 months (range: 0.9–21.5 months). So far, 61 patients have completed induction therapy: first cycle of blinatumomab (n = 55), second cycle (n = 47), third cycle (n = 33), fourth cycle (n = 26), and fifth cycle (n = 17). At the end of induction with dasatinib, 17 of 58 patients had a molecular response (6 complete and 11 cases of positive nonquantifiable disease). At the primary endpoint (end of the second cycle of blinatumomab), 27 of 47 patients (56.3%) had a molecular response (17 complete and 10 cases of positive nonquantifiable disease). The rates of molecular responses further increased after subsequent cycles of blinatumomab: 65.7% after the third cycle and 80% after the fourth cycle.
The ABL1 mutational analysis was carried out in 15 patients with evidence of MRD increase: 8 cases were wild-type, whereas mutations were detected in 7 (6 were T315I and 1 was E255K). All mutations but one occurred prior to the start of blinatumomab, and all were “cleared” by blinatumomab.
Overall, five relapses have been recorded (two hematologic, two isolated central nervous system, and one nodal). The 12-month overall survival and disease-free-survival rates were 94.2% and 87.8%, respectively. A significantly inferior disease-free-survival (61.4%, P = .01) was observed in IKZF1-positive cases: these patients were prone to develop deleterious mutations. So far, 12 patients have been allografted, and no transplant-related mortality has been recorded. Two patients discontinued study treatment, and one patient died during induction treatment.
Clinical Implications: The GIMEMA LAL2116 D-Alba study showed that low-intensity chemotherapy induction and consolidation in BCR-ABL1–positive ALL is feasible and results in excellent outcomes, including high rates of molecular responses with low treatment-related mortality. The limitations of the study include the lack of a comparator arm and the small patient population. Since most patients who completed the study went onto receive an allogeneic hematopoietic cell transplant (allo-HCT), this study leaves unanswered the question of whether an allo-HCT is still necessary for those patients who achieve complete molecular response.
ABSTRACT 823: Phase II study of mini–hyper-CVD in combination with inotuzumab ozogamicin, with or without blinatumomab, in older adults (≥ 60 years) with newly diagnosed (BCR-ABL1–negative) B-cell ALL2
Methods: Patients received mini–hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 for four doses) for up to eight cycles. Inotuzumab ozogamicin was given at a dose of 1.3 to 1.8 mg/m2 on day 3 of cycle 1 and 0.8 to 1.3 mg/m2 on day 3 of cycles 2 to 4. Rituximab (only if CD20-positive; 33 of 58 patients), and prophylactic intrathecal chemotherapy was given for the first four cycles. Responding patients received POMP (mercaptopurine, vincristine, methotrexate, prednisone) maintenance for up to 3 years. To decrease the risk of veno-occlusive disease, the protocol was amended in March 2017 to give inotuzumab ozogamicin in fractionated 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 to administer 4 cycles of blinatumomab following four cycles of mini–hyper-CVD plus inotuzumab ozogamicin, followed by maintenance with 12 cycles of POMP and 4 cycles of blinatumomab (1 cycle of blinatumomab after every 3 cycles of POMP).
Results: Sixty-four patients have been treated, 5 of whom were in complete remission at enrollment. The median age was 68 years (range, 60–81 years); 27 patients were 70 years of age or older. Among 59 patients evaluable for morphologic response, 58 responded (complete remission, n = 51; complete remission with incomplete platelet recovery, n = 6; complete remission with incomplete hematologic recovery, n = 1). MRD negativity by six-color flow cytometry was achieved in 48 of 62 patients after one cycle and 59 of 63 patients overall. There were no early deaths, and the 30-day and 60-day mortality rates were 0% and 3%, respectively.
Among 63 patients who achieved remission, 9 relapsed, 3 underwent allo-HCT in first complete remission, 30 remain on treatment or have completed maintenance, and 21 died in complete remission/complete remission with incomplete platelet recovery. The rate of death in complete remission/complete remission with incomplete platelet recovery was higher in patients 70 years of age and older vs those between the ages of 60 and 69 (P = .02). Approximately six patients developed veno-occlusive disease, one after subsequent allo-HCT. The rate of veno-occlusive disease was 9%, with no difference in patients who did or did not receive blinatumomab. Compared with a similar historical cohort of older adults treated with hyper-CVAD with or without rituximab (n = 77), mini–hyper-CVD plus inotuzumab ozogamicin with or without blinatumomab resulted in significantly higher 3-year overall survival (54% vs 32%; P = .007).
Clinical Implications: Reduced-intensity chemotherapy with mini–hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, is effective in older adults with newly diagnosed (BCR-ABL1–negative) B-cell ALL, with an overall response rate of 98% and 3-year overall survival rate of 54%. According to investigators, further optimization of this regimen with less chemotherapy in patients 70 years of age and older is warranted.
ABSTRACT 739: First analysis of the UKALL14 phase III randomized trial to determine whether the addition of rituximab (irrespective of cell-surface CD20 expression) to standard induction chemotherapy improves event-free survival in adults with precursor B-cell ALL (CRUK/09/006)3
“In relapsed or refractory CD22-positive B-cell ALL, inotuzumab ozogamicin in combination with CVP is relatively well tolerated with low toxicity.”— Syed Ali Abutalib, MD, and Daniel J. DeAngelo, MD, PhD
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Methods: Patients received four doses of rituximab plus the standard-of-care chemotherapy regimen (daunorubicin, vincristine, dexamethasone, and pegylated asparaginase with or without imatinib) in adults ranging from 25 to 65 years. The trial was powered with an 84% chance to detect a 12% improvement in event-free survival (hazard ratio [HR] = 0.71). Rituximab at 375 mg/m2 was given on days 3, 10, 17, and 24. There were 288 patients in the standard-of-care arm and 289 in the standard-of-care-plus-rituximab arm, 273 (95.5%) of whom received all four doses of rituximab. Approximately 86 patients in each arm had BCR-ABL1–positive ALL.
Results: The complete remission rate was 92.7% with the standard of care and 94.8% with the standard of care plus rituximab and did not differ between the two arms. There was no difference in the MRD response between the arms. Likewise, the rate of severe adverse events and nonrelapse mortality did not differ between the arms. At a median follow-up of 50.5 months (7 days–83.6 months), 3-year event-free survival with the standard of care was 41.9% (95% confidence interval [CI] = 35.8%–48.0%) vs with the standard of care plus rituximab 48.7% (CI = 42.4%–54.8%); the hazard ratio was 0.88 (0.71–1.11; P = .28). Of note, the event-free survival hazard ratio for 10% to 20% CD20 expression was 1.74 (0.98–3.10) and more than 20% was 2.20 (1.27–3.81), compared with less than 10% CD20 expression.
Clinical Implications: The study has limitations in the heterogeneous population examined. In addition, limited doses of rituximab (4 vs 16–18 in routine practice) and use of first-generation instead of second-generation tyrosine kinase inhibitors make for a weak argument against the use of rituximab in patients with CD20-positive ALL. We continue to recommend the addition of rituximab in adults with CD20-positive ALL.
Relapsed or Refractory ALL
ABSTRACT 277: SWOG 1312 final results: Phase I study of CVP (cyclophosphamide, vincristine, prednisone) in combination with inotuzumab ozogamicin for relapsed or refractory CD22-positive B-cell ALL (n = 50)4
Methods: All patients (median age of 43-years) received CVP with inotuzumab ozogamicin up to a maximum of six cycles. Each cycle was 28 days. Dose escalation utilized a standard 3+3 design, with the plan to treat 12 additional patients at the maximum tolerated doses. Eighteen patients (38%) had received prior blinatumomab; nine had received prior allo-HCT; 30% had poor-risk cytogenetics, including a few with BCR-ABL1 abnormality. Of 13 patients tested for the Philadelphia chromosome–like signature, it was positive in 5 patients.
Results: Grade 3 or 4 hematologic toxicity related to treatment was common. Grade 3 or 4 nonhematologic toxicity consisted mainly of febrile neutropenia. No cases of hepatic veno-occlusive disease occurred during treatment, but three cases were seen after allo-HCT. Thirteen patients underwent allo-HCT after study treatment. The complete remission with incomplete hematologic recovery rate was 61% (95% CI = 39%–80%) in the 23 evaluable patients treated at the maximum tolerated dose (dose level 5), and 3 of 5 patients with the Philadelphia chromosome–like signature. There was no statistically significant difference in response rates or hepatic toxicities between the various dose levels. However, all three cases of veno-occlusive disease occurred either after the second transplant and/or at dose level 5.
The median overall survival was 7.7 months for all patients and 10.9 months for patients treated at the maximum tolerated dose. Notably, one patient remains in remission 3.5 years out from registration without having a transplant. One death occurred during treatment and was attributed to pneumonia in the setting of active ALL.
Clinical Implications: In relapsed or refractory CD22-positive B-cell ALL, inotuzumab ozogamicin in combination with CVP was tolerable. However, the response rates with CVP plus inotuzumab ozogamicin were not superior to single agent inotuzumab ozogamicin, as reported in the INO-VATE study,5,6 leading to doubts as to the utility of combination chemotherapy plus inotuzumab ozogamicin in the relapsed or refractory setting. Randomized studies will be needed to determine differences in toxicities, response rates, and most important durability with the various combination strategies.
ABSTRACT LBA-1: A randomized phase III trial of blinatumomab vs chemotherapy as post-reinduction therapy in high- and intermediate-risk first relapse of B-cell ALL in children and adolescents/young adults demonstrates superior efficacy and tolerability of blinatumomab: A report from Children’s Oncology Group Study AALL13317
“The AALL1331 trial established blinatumomab as a new standard of care for consolidation therapy in patients between the ages of 1 and 30 with high-risk and intermediate-risk relapsed diseases.”— Syed Ali Abutalib, MD, and Daniel J. DeAngelo, MD, PhD
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Methods: High-risk disease was defined as early relapse, within 3 years of diagnosis, if the relapse occurred in the bone marrow or isolated extramedullary relapse within 18 months from diagnosis. Intermediate-risk disease was defined as late relapse and MRD of at least 0.1% at the end of re-induction chemotherapy. All patients received re-induction chemotherapy (block 1 of UKALLR3/mitoxantrone arm) prior to randomization. A total of 208 patients (median age = 9 years; age range = 1–29 years) were enrolled and randomly assigned to one of two arms. Arm A included two intensive consolidation chemotherapy blocks (dexamethasone, mitoxantrone, methotrexate, pegylated asparaginase, vincristine; n = 103), and arm B included two 4-week blocks of blinatumomab, with each block followed by 1 week of rest (n = 105). Patients in both arms were scheduled to proceed to HCT after consolidation.
Results: After a median follow-up of 1.4 years, the 2-year disease-free survival (primary endpoint) rate was significantly higher in the blinatumomab arm: 59.3% vs 41.0% (P = .05). The rate of 2-year overall survival, a secondary endpoint, also was higher with blinatumomab vs standard chemotherapy: 79.4% vs 59.2% (P = .005).
Clinical Implications: The AALL1331 trial established blinatumomab as a new standard of care for consolidation therapy in patients between the ages of 1 and 30 with high-risk and intermediate-risk relapse diseases. The major question left unanswered is whether the initial block of re-induction chemotherapy is required prior to the administration of blinatumomab.
DISCLOSURE: Dr. Abutalib has served on advisory boards for AstraZeneca and Partner Therapeutics. Dr. DeAngelo has served as a consultant or advisor to Amgen, Blueprint Medicines, Bristol-Myers Squibb, Celgene, Immunogen, Incyte, Novartis, Pfizer, and Takeda; and has received institutional research funding from AbbVie, Blueprint Medicines, Glycomimetics, and Novartis.
REFERENCES
1. Chiaretti S, Bassan R, Vitale A, et al: Dasatinib-blinatumomab combination for the front-line treatment of adult Ph+ ALL patients: Updated results of the GIMEMA LAL2116 D-Alba trial. 2019 ASH Annual Meeting & Exposition. Abstract 740. Presented December 10, 2019.
2. Short NJ, Kantarjian HM, Ravandi F, et al: Updated results of a phase II study of reduced-intensity chemotherapy with mini-hyper-CVD in combination with inotuzumab ozogamicin, with or without blinatumomab, in older adults with newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukemia. 2019 ASH Annual Meeting & Exposition. Abstract 823. Presented December 10, 2019.
3. Marks DI, Kirkwood AA, Rowntree CJ, et al: First analysis of the UKALL14 phase 3 randomised trial to determine if the addition of rituximab to standard induction chemotherapy improves EFS in adults with precursor B-ALL (CRUK/09/006). 2019 ASH Annual Meeting & Exposition. Abstract 739. Presented December 10, 2019.
4. Advani AS, Moseley A, Liedtke M, et al: SWOG 1312 final results: A phase 1 trial of inotuzumab in combination with CVP (cyclophosphamide, vincristine, prednisone) for relapsed/refractory CD22+ acute leukemia. 2019 ASH Annual Meeting & Exposition. Abstract 227. Presented December 10, 2019.
5. Kantarjian HM, DeAngelo DJ, Stelljes M, et al: Inotuzumab ozogamicin vs standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer 125:2474-2487, 2019.
6. Kantarjian HM, DeAngelo DJ, Stelljes M, et al: Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 375:740-753, 2016.
7. Brown PA, Ji L, Xu X, et al: A randomized phase 3 trial of blinatumomab vs. chemotherapy as post-reinduction therapy in high and intermediate risk first relapse of B-acute lymphoblastic leukemia in children and adolescents/young adults demonstrates superior efficacy and tolerability of blinatumomab: A report from Children’s Oncology Group Study AALL1331. 2019 ASH Annual Meeting & Exposition. Abstract LBA-1. Presented December 10, 2019.
