Long-term follow-up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome–positive B-cell precursor acute lymphoblastic leukaemia: Final analysis of ALCANTARA study

Martinelli, Giovanni; Boissel, Nicolas; Chevallier, Patrice; Ottmann, Oliver G.; Gökbuget, Nicola; Rambaldi, Alessandro; Ritchie, Ellen K.; Papayannidis, Cristina; Tuglus, Catherine; Morris, Joan; Stein, Anthony S.

doi:10.1016/j.ejca.2020.12.022

Cited by 50 publications

(51 citation statements)

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“…21 We noted a CR/CRi rate of 83% which was comparable to the CR/CRi rate of 73% with inotuzumab ozogamicin alone in Ph + ALL patients in the INO-VATE ALL trial 9 and favorable compared to 36% with blinatumomab alone in the ALCANTARA trial. 10,11 The median EFS of 7.7 months with the combination of inotuzumab ozogamicin and bosutinib is favorable compared to 3.9 months with single agent inotuzumab ozogamicin. 9 Similarly, the median OS of 13.5 months in this trial appears superior to 8.7 months with inotuzumab ozogamicin 9 and 9.0 months with blinatumomab in a similar patient population.…”

Section: Discussionmentioning

confidence: 99%

“…9 Similarly, the median OS of 13.5 months in this trial appears superior to 8.7 months with inotuzumab ozogamicin 9 and 9.0 months with blinatumomab in a similar patient population. 10,11 However, given our overall results and challenges comparing results across trial, the benefit of addition of bosutinib to inotuzumab ozogamicin remains unclear, at least in terms of CR/CRi rate. It is possible that the addition of bosutinib can potentially improve EFS, DOR and OS; however, prospective randomized comparisons are needed to establish such benefit.…”

Section: Discussionmentioning

confidence: 99%

“…Three patients were treated at dose level one (bosutinib 300 mg daily), six patients at dose level two (bosutinib 400 mg daily), and nine patients at dose level three (bosutinib 500 mg daily). One patient had a dose limiting toxicity (DLT) of grade three skin rash at dose level two, and two patients had DLTs of grade three skin rash at dose Patients received a median of three cycles of therapy (range, [1][2][3][4][5][6][7][8][9][10][11]. Patients received a median 3.9 mg/m 2 (range, 1.8-6.8) total cumulative dose of inotuzumab ozogamicin.…”

Section: Safetymentioning

confidence: 99%

“…9 In the ALCANTARA trial, 45 patients with R/R Ph + ALL received single agent blinatumomab. 10,11 The CR/CRi rate was 36% with 88% of responders (31% overall) achieved complete molecular response (CMR). The median OS was 9.0 months and the median relapse-free survival (RFS) among responders was 6.8 months.…”

Section: Introductionmentioning

confidence: 99%

“…In a post‐hoc analysis, 16/22 (73%) achieved complete response (CR) / CR with incomplete count recovery (CRi) with a median progression‐free survival (PFS) of 3.9 months and a median overall survival (OS) of 8.7 months 9 . In the ALCANTARA trial, 45 patients with R/R Ph + ALL received single agent blinatumomab 10,11 . The CR/CRi rate was 36% with 88% of responders (31% overall) achieved complete molecular response (CMR).…”

Section: Introductionmentioning

confidence: 99%

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Inotuzumab ozogamicin with bosutinib for relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia or lymphoid blast phase of chronic myeloid leukemia

et al. 2021

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Relapsed/refractory (R/R) Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) and lymphoid blast phase of chronic myeloid leukemia (LBP-CML) have poor outcomes. We designed a phase 1/2 study combining inotuzumab ozogamicin with bosutinib for this patient population. Patients with T315I mutation were excluded. Bosutinib was administered daily at three dose levels (300 mg/d, 400 mg/d, 500 mg/d) in a 3 + 3 design. Inotuzumab ozogamicin was dosed weekly during cycle one, and once every 4 weeks subsequently for a total of six cycles. The primary objective was to determine the safety and the maximum tolerated dose (MTD) of bosutinib in combination with inotuzumab ozogamicin. Eighteen patients were enrolled (Ph-positive ALL, n = 16; LBP-CML, n = 2). The median age was 62 years (range, 19-74) and the median number of prior therapies was one (range, 1-5). Dose limiting toxicities included grade 3 skin rash and bosutinib 400 mg daily was determined as the MTD. The most frequent grade 3/4 treatment-emergent adverse events were thrombocytopenia (60%) and neutropenia (38%). A complete response (CR) / CR with incomplete count recovery (CRi) was achieved in 15/18 (83%) patients; 11/18 (61%) patients achieved negative measurable residual disease by flow cytometry. Complete molecular response was noted in 10/18 (56%) patients.The 30-day mortality was 0%. After a median follow-up of 44 months, the median duration of response and overall survival were 7.7 months and 13.5 months, respectively. Six patients had a subsequent allogeneic stem cell transplant. No patient developed veno-occlusive disease. Inotuzumab ozogamicin with bosutinib was well

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Safetymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inotuzumab ozogamicin with bosutinib for relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia or lymphoid blast phase of chronic myeloid leukemia

et al. 2021

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Treatment of Adults With Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia—From Intensive Chemotherapy Combinations to Chemotherapy-Free Regimens

2022

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Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) is now a relatively favorable-risk acute leukemia. In this review, we discuss the current evidence for frontline therapies of Ph-positive ALL, the major principles that guide therapy, and the progress with chemotherapy-free regimens.OBSERVATIONS Incorporating TKIs into the chemotherapy regimens of patients with newly diagnosed Ph-positive ALL has led to improved remission rates, higher probability of reaching allogeneic stem cell transplantation (SCT), and longer survival compared with chemotherapy alone. Early achievement of a complete molecular remission (CMR) is an important end point in Ph-positive ALL and identifies patients who have excellent long-term survival and may not need allogeneic SCT. Second-generation TKIs combined with intensive or low-intensity chemotherapy resulted in higher CMR rates compared with imatinib-based regimens. This translated into better outcomes, with less reliance on allogeneic SCT. To further improve the outcomes, the potent third-generation TKI ponatinib was added to chemotherapy. The combination of hyper-CVAD and ponatinib resulted in an overall CMR rate of 84% and a 5-year survival rate of 73% and 86% among patients who did and did not undergo allogeneic SCT, respectively, suggesting that allogeneic SCT may not be needed with this regimen. The recent chemotherapy-free combination of dasatinib and blinatumomab was safe and effective in patients with newly diagnosed Ph-positive ALL and resulted in an estimated 3-year OS rate of 80%; 50% of patients underwent allogeneic SCT. The chemotherapy-free regimen of ponatinib and blinatumomab resulted in a CMR rate of 86% and a 2-year survival rate of 93%, with no relapses or leukemia-related deaths, and with only 1 patient proceeding to allogeneic SCT. CONCLUSIONS AND RELEVANCEThe promising results obtained with the chemotherapy-free regimens of blinatumomab plus TKIs question the role of allogeneic SCT in first remission. Patients with Ph-positive ALL who achieve early and deep molecular responses have excellent long-term outcomes and may not benefit from allogeneic SCT.

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Extramedullary disease relapse and progression after blinatumomab therapy for treatment of acute lymphoblastic leukemia

Aldoss

Otoukesh

Zhang

et al. 2021

Cancer

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BACKGROUND: Blinatumomab has demonstrated encouraging activity in relapsed/refractory (r/r) and minimal residual disease-positive (MRD+) acute lymphoblastic leukemia (ALL). Extramedullary disease (EMD) relapse or relapse with CD19-disease has been observed after blinatumomab therapy in patients with r/r or MRD+ ALL. However, the pathophysiology and risk factors of treatment failure are not fully understood. METHODS: This study retrospectively reviewed the outcomes of adult patients with B-cell ALL treated with blinatumomab (n = 132) for either r/r (n = 103) or MRD+ disease (n = 29) at the authors' center (2013-2021) and analyzed factors associated with treatment response and EMD failure. RESULTS: The overall response rate was 64%. A lower marrow blast burden before blinatumomab (P = .049) and no history of previous EMD (P = .019) were significantly associated with a higher response. Among the patients who responded to blinatumomab, 56% underwent consolidation with allogeneic transplantation. Blinatumomab failure was observed in 89 patients; 43% of these patients (n = 38) either progressed or relapsed at extramedullary sites. A history of extramedullary involvement (53% vs 24%; P = .005) and retention of CD19 expression at the time of relapse/progression (97% vs 74%; P = .012) were associated with a higher risk for extramedullary failure. Central nervous system (CNS) failure after blinatumomab was encountered in 39% of the patients with EMD. CONCLUSIONS: A history of EMD predicted an inferior response to blinatumomab therapy with a higher risk for relapse/ progression at extramedullary sites (particularly CNS). Consolidation with allogenic transplantation in patients who primarily responded to blinatumomab did not abrogate the risk of extramedullary relapse. The incorporation of extramedullary assessment and the intensification of CNS prophylaxis may help in addressing extramedullary failure.

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Long-term follow-up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome–positive B-cell precursor acute lymphoblastic leukaemia: Final analysis of ALCANTARA study

Cited by 50 publications

References 21 publications

Inotuzumab ozogamicin with bosutinib for relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia or lymphoid blast phase of chronic myeloid leukemia

Inotuzumab ozogamicin with bosutinib for relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia or lymphoid blast phase of chronic myeloid leukemia

Treatment of Adults With Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia—From Intensive Chemotherapy Combinations to Chemotherapy-Free Regimens

Extramedullary disease relapse and progression after blinatumomab therapy for treatment of acute lymphoblastic leukemia

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