Does the New Treatment Landscape in Adult ALL Replace Chemotherapy With Targeted Therapies?

Matthew J. Wieduwilt, MD, PhD

Traditional cytotoxic chemotherapy-containing regimens have been the backbone of treatment for adults with acute lymphoblastic leukemia (ALL) for decades. Common complications of traditional chemotherapy can be fatal and include infection, bleeding, thrombosis, neuropathy, osteonecrosis, and secondary cancers including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Compared with children with ALL, response rates and cure rates are substantially lower in adults. For patients over 60 years of age, traditional cytotoxic chemotherapy yields low cure rates, high treatment-related death rates, and poor long-term survival of < 20%. For older adults, there has been minimal improvement in survival over the last 40 years despite marked improvement for adults under 60 years, adolescents, and children.¹ For older patients, traditional chemotherapy approaches have largely failed.

Because the balance between efficacy and toxicity of chemotherapy has been reached for most adults with ALL, novel approaches with highly active, minimally toxic agents are needed to improve on traditional chemotherapy and possibly eliminate chemotherapy altogether. This unmet need was addressed during the Society of Hematologic Oncology 2021 Annual Meeting.

Tyrosine kinase inhibitors (TKIs) for Philadelphia-chromosome positive (Ph+) ALL, the anti-CD22- calicheamicin antibody-drug conjugate inotuzumab ozogamicin (Besponsa) for relapsed/refractory (R/R) B-cell ALL, and the anti-CD3/CD19 bifunctional T-cell engaging antibody blinatumomab (Blincyto) for R/R B-cell ALL have transformed care for ALL. Inotuzumab ozogamicin and blinatumomab are both superior for remission rates and survival compared with traditional chemotherapy in phase 3 studies in R/R B-cell ALL.^2,3 Inotuzumab ozogamicin yielded high complete response rates (81%) and minimal residual disease (MRD)-negativity rates (78%) but with short median duration of remission (DOR; 4.6 months).² Blinatumomab had a lower complete response (CR) rate than inotuzumab ozogamicin (44%) but a longer median DOR (7.3 months) and was found most effective in patients with low-burden disease in the marrow (lymphoblasts < 50%, CR rate 66%), suggesting that blinatumomab may be a highly effective agent in consolidation of remission in the frontline.³

Why Avoid Traditional Systemic Chemotherapy?

There are multiple answers that are appropriate: Traditional chemotherapy alone (1) is ineffective in most patients with certain types of ALL (such as Ph+ ALL); (2) has a high treatment-related mortality with low cure rates in older patients; (3) requires extended, complicated, and toxic treatment for 3 to 4 years; (4) is often only a bridge to allogeneic hematopoietic cell transplantation (HCT), which has a high rate of treatment-related morbidity and mortality; and (5) has long-term morbidity independent of allogeneic HCT including osteonecrosis of the bone, neuropathy, neurocognitive changes, and secondary cancers. Novel targeted agents are more active than traditional chemotherapy in ALL and maximizing their use in the front line may yield similar or superior results, even when combined with reduced-dose or no chemotherapy. Adding new agents to traditional chemotherapy also may lead to inferior outcomes as targeted agent doses are frequently reduced for toxicity when given in combination with chemotherapy and the combinations can have high non-relapse mortality that may erase any benefit of increased efficacy from adding the novel agent.⁴

The Philadelphia (Ph) chromosome occurs from translocation of chromosomes 9 and 22, which generates a BCR-ABL1 oncogenic fusion protein with constitutive tyrosine kinase activity and is the genetic hallmark of chronic myeloid leukemia (CML) and Ph+ ALL. Ph+ ALL was historically a poor-risk disease in adults with long-term survival less than 20% with chemotherapy alone.^5-7

Tyrosine Kinase Inhibitors

The development and application of BCR-ABL1—targeted tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (Gleevec), dasatinib (Sprycel), and ponatinib (Inclusig) in CML and Ph+ ALL has dramatically changed care and improved survival. Early study of imatinib with chemotherapy improved survival.7 Without allogeneic HCT most patients treated with imatinib relapsed due in large part to numerous different mutations in the BCR-ABL1 kinase domain (KD).

Second-generation TKIs such as dasatinib overcome most TKI resistance by BCR-ABL1 KD mutation although they are ineffective against the T315I mutation seen in 70% to 75% of relapses in dasatinib-treated patients.^8-10 The combination of second-generation TKIs with intensive chemotherapy appears to lead to superior outcomes to imatinib-based approaches. SWOG 0805 (NCT00792948) studied dasatinib with hyper cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HyperCVAD) in adults 60 years of age and younger with Ph+ ALL. Patients undergoing allogeneic HCT after dasatinib/ HyperCVAD induction had better survival than those receiving dasatinib and chemotherapy alone, supporting allogeneic HCT in this population.¹¹ Ponatinib has been studied in combination with HyperCVAD. The combination was highly active with a complete response (CR) rate of 100%, complete molecular response (CMR) rate of 78%, and 3-year event free survival (EFS) of 70%.^12,13

Rationale for Reducing or Eliminating Chemotherapy

The toxicities of these intensive approaches are typically prohibitive for use in older adults with Ph+ ALL. Given the high activity of BCR-ABL1–targeted TKIs in Ph+ ALL, approaches to reduce treatment-related mortality have been studied by reducing or eliminating chemotherapy. GRAAPH-2005 (NCT00327678) randomized patients to imatinib with HyperCVAD or with minimal chemotherapy. The CR rate was higher with the minimal chemotherapy approach (98% vs 91%, P = .006) principally because of increase induction death with HyperCVAD.¹⁴

Studies of chemotherapy-free induction with TKIs with corticosteroids showed that the approach yields CR rates of 95% to 100% with no or minimal induction death. GIMEMA study LAL1205 (NCT00391989) evaluated dasatinib with prednisone followed by provider choice of post remission therapy. The regimen was well tolerated with a CR rate of 93%. Relapse occurred in 74%, 36%, 11% of patients getting post-remission therapy with TKI only, TKI with chemotherapy, and allogeneic HCT, respectively.⁸ A subsequent GIMEMA study, the D-ALBA study (NCT02744768), evaluated dasatinib and blinatumomab for 5 cycles, then dasatinib maintenance as post remission therapy after dasatinib/corticosteroid induction. The CR rate was 98% with excellent 18-month overall survival (OS) and disease-free survival (DFS) of 95% and 88%, respectively.¹⁵ At last report with 27 months follow-up, there were 9 relapses among 63 patients (4 systemic, 4 CNS, 1 nodal).¹⁶ Confirmatory data are awaited from the ongoing US Intergroup SWOG 1318 study (NCT02143414), which has completed accrual. The failing of dasatinib due to BCR-ABL1 T315I ALL is being addressed by treating older patients with ponatinib and corticosteroids alone. An early report showed a high CR rate (95%) and favorable molecular response rate (CMR rate 46%) with short follow-up.¹⁷ More recently, investigators reported early outcomes of ponatinib with blinatumomab. In newly diagnosed patients, the CR rate was 100%, CMR rate was 87%, and estimated 1-year OS and DFS were both 100%.18 Long-term follow up is needed for durability of responses and late toxicity.

Ph-Negative ALL

The road to chemotherapy-free regimens in Ph-negative ALL is just being paved given the recent availability of highly effective targeted therapies. For Ph-negative ALL, inotuzumab ozogamicin and blinatumomab are being actively studied in randomized studies in the front line (eg, A041501 NCT03150693, EA1910 NCT 02003222). Given their impressive activity, studies are also evaluating them in chemotherapy-free induction or as chemotherapy-free regimens. SWOG 1318 evaluated blinatumomab as induction therapy for older, transplant-ineligible patients. The regimen was very well tolerated with a CR rate of 66%, MRD negativity rate of 92%, and a 1-year DFS of 56%.¹⁹ Inotuzumab ozogamicin has demonstrated a 100% CR rate and MRD negativity rate of 74% as induction in GMALL INITIAL-1 trial (NCT03460522).²⁰ Alliance A041703 (NCT03739814) is studying inotuzumab ozogamicin followed by consolidation with 4 to 5 cycles of blinatumomab in older patients with results expected in 2022.

Advancements in chemotherapy-free regimens are improving outcomes in Ph-positive ALL and hold promise in Ph-negative ALL. Clinical trials have been and remain essential to continuing the transformative progress. Questions will need to be answered including the optimal CNS pro-phylaxis, need for and/or duration of maintenance, antigen levels conferring benefit, the benefit of adding novel agents including BH3 mimetics such as venetoclax (Venclexta) or navitoclax, anti-bodies such as daratumumab (Darzalex), and checkpoint inhibitors, and mechanisms of resistance to inform future development of these therapies. It is hoped “chemo-free” approaches will set a new standard of care and form a backbone on which to build even more effective, highly tolerable, and convenient therapies with very high cure rates.

_REFERENCES:

_{1. Sasaki K, Jabbour E, Short NJ, et al. Acute lymphoblastic leukemia: a population-based study of outcome in the United States based on the surveillance, epidemiology, and end results (SEER) database, 1980- 2017. Am J Hematol. 2021;96(6):650-658. doi:10.1002/ajh.26156}

_{2. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753. doi:10.1056/NEJMoa1509277}

_{3. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847. doi:10.1056/NEJMoa1609783}

_{4. Short NJ, Kantarjian HM, Ravandi F, et al. Reduced-intensity chemotherapy with mini-Hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in older adults with newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukemia: results from a Phase II study. Blood. 2020;136(suppl 1):15-17. doi: 10.1182/ blood-2020-138569}

_{5. Larson RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995;85(8):2025-2037.}

_{6. Kantarjian HM, O’Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000;18(3):547-561. doi:10.1200/ JCO.2000.18.3.547}

_{7. Fielding AK, Rowe JM, Buck G, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014;123(6):843-850. doi:10.1182/blood-2013-09-529008}

_{8. Foà R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011;118(25):6521-6528. doi:10.1182/ blood-2011-05-351403}

_{9. Rousselot P, Coudé MM, Gokbuget N, et al. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. Blood. 2016;128(6):774-782. doi:10.1182/ blood-2016-02-700153}

_{10. Wieduwilt MJ, Yin J, Wetzler M, et al. A phase II study of dasatinib and dexamethasone as primary therapy followed by transplantation for adults with newly diagnosed Ph/BCR-ABL1-positive acute lymphoblastic leukemia (Ph+ ALL): Final results of Alliance/CALGB study 10701. Blood. 2018;132(suppl 1):309. doi:10.1182/blood-2018-99-120029}

_{11. Ravandi F, Othus M, O’Brien SM, et al. US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv. 2016;1(3):250- 259. doi:10.1182/bloodadvances.2016001495}

_{12. Jabbour E, Kantarjian H, Ravandi F, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015;16(15):1547-1555. doi:10.1016/S1470-2045(15)00207-7}

_{13. Jabbour E, Short NJ, Ravandi F, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study. Lancet Haematol. 2018;5(12):e618-e627. doi:10.1016/S2352-3026(18)30176-5}

_{14. Chalandon Y, Thomas X, Hayette S, et al. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015;125(24):3711- 3719. doi:10.1182/blood-2015-02-627935}

_{15. Foà R, Bassan R, Vitale A, et al. Dasatinib-blinatumomab for pH-positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383(17):1613-1623. doi:10.1056/NEJMoa2016272}

_{16. Chiaretti S, Bassan R, Vitale A, et al. Updated results of the GIMEMA LAL2116, D-ALBA trial, for newly diagnosed adults with Ph+ ALL. EHA Library. June 9, 2021. Accessed August 17, 2021. https:// library.ehaweb.org/eha/2021/eha2021-virtual-congress/324520/ sabina.chiaretti.updated.results.of.the.gimema.lal2116.d-alba.trial. for.newly.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3Ds112}

_{17. Martinelli G, Piciocchi A, Papayannidis C, et al. First report of the GIMEMA LAL1811 phase II prospective study of the combination of steroids with ponatinib as frontline therapy of elderly or unfit patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2017;130(suppl 1):99. doi:10.1182/blood.V130. Suppl_1.99.99}

_{18. Short NJ, Kantarjian HM, Konopleva M, et al. Combination of ponatinib and blinatumomab in Philadelphia chromosome-positive acute lymphoblastic leukemia: Early results from a phase II study. J Clin Oncol. 2021;39(suppl 15):7001-7001. doi:10.1200/ JCO.2021.39.15_suppl.7001}

_{19. Advani AS, Anna Moseley A, O’Dwyer KM, et al. Results of SWOG 1318: A phase 2 trial of blinatumomab followed by POMP (prednisone, vincristine, methotrexate, 6-mercaptopurine) maintenance in elderly patients with newly diagnosed Philadelphia chromosome negative B-cell acute lymphoblastic leukemia. Blood. 2018;132(suppl 1):33. doi:10.1182/blood-2018-99-111992}

_{20. Stelljes M, Raffel S, Wäsch R, et al. First results of an open label phase II study to evaluate the efficacy and safety of inotuzumab ozogamicin for induction therapy followed by a conventional chemotherapy based consolidation and maintenance therapy in patients aged 56 years and older with acute lymphoblastic leukemia (INITIAL-1 trial). Blood. 2020;136(suppl 1):12-13. doi:10.1182/blood-2020-136920}