An effective chemotherapy‐free regimen of ponatinib plus venetoclax for relapsed/refractory <scp>P</scp>hiladelphia chromosome‐positive acute lymphoblastic leukemia

Short, Nicholas J.; Konopleva, Marina; Kadia, Tapan M.; Kebriaei, Partow; Huang, Xuelin; Masárová, Lucia; Cook, Robin; Jain, Nitin; Kantarjian, Hagop M.; Ravandi, Farhad

doi:10.1002/ajh.26175

Cited by 22 publications

(10 citation statements)

References 14 publications

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“…This observation is consistent with results from other studies, 25,46 suggesting that a non-BCR-ABL1dependent mechanism of resistance underlies most relapses. T315L was previously shown to confer resistance to ponatinib, 47 and it is sensitive to axitinib in vitro. 48,49 Future studies are needed to evaluate mechanisms of relapse for patients with Ph + ALL treated with ponatinib-based regimens.…”

Section: Resultsmentioning

confidence: 99%

“…46 Moreover, the combination of ponatinib, venetoclax, and dexamethasone has demonstrated early clinical efficacy in heavily pretreated patients with relapsed/refractory Ph + ALL (complete remission or complete remission with incomplete hematologic recovery in 5/6 [83%] patients who received venetoclax 800 mg). 47 Combinations of the bispecific anti-CD3/CD19 monoclonal antibody blinatumomab with TKIs (ponatinib, dasatinib, or bosutinib) have also shown efficacy in the treatment of Ph + ALL, with high rates of CMR and favorable survival outcomes. 45,48,49 Taken together, these findings suggest that combining TKIs with steroids and/or other nonchemotherapy agents may be an effective strategy to avoid chemotherapy without compromising efficacy in patients with Ph + ALL.…”

Section: Resultsmentioning

confidence: 99%

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INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia

et al. 2022

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Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL aged ≥60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/day for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/day from days -14 to 29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) was reached in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of April 24, 2020, median event-free survival was 14.31 months (95% CI 9.30, 22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increased (15.9%), erythema (15.9%), and gamma-glutamyltransferase increased (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade ≥3, 18.2%) and 27.3% (grade ≥3, 15.9%) of patients, respectively. Dose reductions/interruptions/discontinuations due to TEAEs occurred in 43.2%/43.2%/27.3% of patients; 5 patients had fatal TEAEs. Ponatinib and prednisone had efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. (This trial is registered at www.clinicaltrials.gov as NCT01641107).

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia

et al. 2022

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“…Several pre-clinical studies suggested that dual targeting of pro-survival BCL2 signaling and BCR-ABL with the combination of venetoclax and a TKI may have an anti-leukemic effect and prevent resistance in the Ph+ ALL setting [ 143 , 144 , 145 ]. Combination of ponatinib, venetoclax and dexamethasone (VPD regimen) was evaluated in a phase 1/2 clinical trial that enrolled 9 patients with R/R Ph+ ALL [ 146 ]. Three patients received venetoclax at the dosage of 400 mg daily and 6 patients at the dosage of 800 mg daily.…”

Section: Treatment Of Relapsed/refractory Ph+ All Patientsmentioning

confidence: 99%

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults

Saleh

Fernández

Pasquier

2022

Cancers

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Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) is the most common subtype of B-ALL in adults and its incidence increases with age. It is characterized by the presence of BCR-ABL oncoprotein that plays a central role in the leukemogenesis of Ph+ ALL. Ph+ ALL patients traditionally had dismal prognosis and long-term survivors were only observed among patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). However, feasibility of allo-HSCT is limited in this elderly population. Fortunately, development of increasingly powerful tyrosine kinase inhibitors (TKIs) from the beginning of the 2000′s dramatically improved the prognosis of Ph+ ALL patients with complete response rates above 90%, deep molecular responses and prolonged survival, altogether with good tolerance. TKIs became the keystone of Ph+ ALL management and their great efficacy led to develop reduced-intensity chemotherapy backbones. Subsequent introduction of blinatumomab allowed going further with development of chemo free strategies. This review will focus on these amazing recent advances as well as novel therapeutic strategies in adult Ph+ ALL.

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“…Preclinical evidence also suggests that Ph-positive ALL is highly dependent on Bcl-2 for survival, supporting a potential role for venetoclax in this setting [44]. Initial results in nine patients from a phase I/II study of the oral combination of ponatinib, venetoclax and dexamethasone showed a CR/CRi rate of 56% and CMR rate of 44% in a heavily pretreated population of patients with relapsed/ refractory Ph-positive ALL (78% with prior ponatinib, 56% with prior blinatumomab, and 67% with prior HSCT) [45]. With a median follow-up of 13.2 months, the median OS was not reached and none of the five responding patients had relapsed.…”

Section: Other Novel Therapiesmentioning

confidence: 99%

Optimizing the treatment of acute lymphoblastic leukemia in younger and older adults: new drugs and evolving paradigms

2021

Self Cite

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In the past decade, the available treatments for patients with acute lymphoblastic leukemia (ALL) have rapidly expanded, in parallel with an increased understanding of the genomic features that impact the disease biology and clinical outcomes. With the development of the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin, the CD3-CD19 bispecific T-cell engager antibody blinatumomab, CD19 chimeric antigen receptor T-cell therapy, and the potent BCR-ABL1 tyrosine kinase inhibitor ponatinib, the outlook of ALL in both younger and older adults has substantially improved. The availability of highly effective drugs raised important questions concerning the optimal combination and sequence of these agents, their incorporation into frontline regimens, and the role of hematopoietic stem cell transplantation. In this review, we discuss the rapidly evolving paradigms in the treatment of ALL, highlighting both established and effective regimens, as well as promising new therapies that are being evaluated in ongoing clinical trials. We specifically focus on novel combination regimens in both the frontline and salvage settings that are leading to new standards of care in the treatment of ALL.

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An effective chemotherapy‐free regimen of ponatinib plus venetoclax for relapsed/refractory Philadelphia chromosome‐positive acute lymphoblastic leukemia

Cited by 22 publications

References 14 publications

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults

Optimizing the treatment of acute lymphoblastic leukemia in younger and older adults: new drugs and evolving paradigms

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