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DOSE-ADJUSTED EPOCH + INOTUZUMAB OZOGAMICIN (DA-EPOCH-INO) IS SAFE AND ACTIVE IN ADULTS WITH RELAPSED/REFRACTORY (R/R) B LYMPHOBLASTIC LEUKEMIA (B-ALL): INITIAL RESULTS OF A PHASE I TRIAL
Author(s): ,
Ryan Cassaday
Affiliations:
University of Washington,Seattle,États-unis;University of Washington,Seattle,Vereinigte Staaten;University of Washington,Seattle,Stati Uniti;University of Washington,Seattle,United States;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,Verenigde Staten;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,United States;University of Washi
,
Kelsey-Leigh Garcia
Affiliations:
University of Washington,Seattle,États-unis;University of Washington,Seattle,Vereinigte Staaten;University of Washington,Seattle,Stati Uniti;University of Washington,Seattle,United States;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,Verenigde Staten;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,United States;University of Washi
,
Ted Gooley
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,États-unis;Fred Hutchinson Cancer Research Center,Seattle,Vereinigte Staaten;Fred Hutchinson Cancer Research Center,Seattle,Stati Uniti;Fred Hutchinson Cancer Research Center,Seattle,United States;Fred Hutchinson Cancer Research Center,Seattle,Estados Unidos;Fred Hutchinson Cancer Research Center,Seattle,Verenigde Staten;Fred Hutchinson Cancer Researc
,
Christen Martino
Affiliations:
Seattle Cancer Care Alliance,Seattle,États-unis;Seattle Cancer Care Alliance,Seattle,Vereinigte Staaten;Seattle Cancer Care Alliance,Seattle,Stati Uniti;Seattle Cancer Care Alliance,Seattle,United States;Seattle Cancer Care Alliance,Seattle,Estados Unidos;Seattle Cancer Care Alliance,Seattle,Verenigde Staten;Seattle Cancer Care Alliance,Seattle,Estados Unidos;Seattle Cancer Care Alliance,Seattle,U
,
Mary-Elizabeth Percival
Affiliations:
University of Washington,Seattle,États-unis;University of Washington,Seattle,Vereinigte Staaten;University of Washington,Seattle,Stati Uniti;University of Washington,Seattle,United States;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,Verenigde Staten;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,United States;University of Washi
,
Anna Halpern
Affiliations:
University of Washington,Seattle,États-unis;University of Washington,Seattle,Vereinigte Staaten;University of Washington,Seattle,Stati Uniti;University of Washington,Seattle,United States;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,Verenigde Staten;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,United States;University of Washi
,
Vivian Oehler
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,États-unis;Fred Hutchinson Cancer Research Center,Seattle,Vereinigte Staaten;Fred Hutchinson Cancer Research Center,Seattle,Stati Uniti;Fred Hutchinson Cancer Research Center,Seattle,United States;Fred Hutchinson Cancer Research Center,Seattle,Estados Unidos;Fred Hutchinson Cancer Research Center,Seattle,Verenigde Staten;Fred Hutchinson Cancer Researc
,
Janis Abkowitz
Affiliations:
University of Washington,Seattle,États-unis;University of Washington,Seattle,Vereinigte Staaten;University of Washington,Seattle,Stati Uniti;University of Washington,Seattle,United States;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,Verenigde Staten;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,United States;University of Washi
,
Roland Walter
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,États-unis;Fred Hutchinson Cancer Research Center,Seattle,Vereinigte Staaten;Fred Hutchinson Cancer Research Center,Seattle,Stati Uniti;Fred Hutchinson Cancer Research Center,Seattle,United States;Fred Hutchinson Cancer Research Center,Seattle,Estados Unidos;Fred Hutchinson Cancer Research Center,Seattle,Verenigde Staten;Fred Hutchinson Cancer Researc
,
Cristina Ghiuzeli
Affiliations:
University of Washington,Seattle,États-unis;University of Washington,Seattle,Vereinigte Staaten;University of Washington,Seattle,Stati Uniti;University of Washington,Seattle,United States;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,Verenigde Staten;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,United States;University of Washi
Elihu Estey
Affiliations:
University of Washington,Seattle,États-unis;University of Washington,Seattle,Vereinigte Staaten;University of Washington,Seattle,Stati Uniti;University of Washington,Seattle,United States;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,Verenigde Staten;University of Washington,Seattle,Estados Unidos;University of Washington,Seattle,United States;University of Washi
(Abstract release date: 05/12/22) EHA Library. Cassaday R. 06/10/22; 357214; P351
Ryan Cassaday
Ryan Cassaday
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P351

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Clinical

Background
Despite new drugs, survival with R/R B-ALL remains poor. Combination therapies may improve outcomes, but none are proven superior, and toxicities may pose limits. InO has been added to low-intensity chemotherapy, but the risks/benefits of such combinations are poorly defined. As we recently found DA-EPOCH to be effective for untreated ALL, we here tested the addition of InO to DA-EPOCH (#NCT03991884).

 

Aims
The primary objective was to estimate the maximum tolerated dose (MTD) of InO when added to DA-EPOCH.

 

Methods
Eligible adults had R/R CD22+ B-ALL with ≥5% blasts in blood/marrow or ≥1 site of extramedullary disease [EMD] ≥1.5 cm in diameter. No history of sinusoidal obstructive syndrome (SOS) or chronic liver disease was allowed. Other key eligibility criteria included bilirubin ≤1.5x upper limit of normal (ULN), AST/ALT ≤2.5x ULN, creatinine ≤1.5x ULN, QTc ≤500 msec, and ECOG 0-2. All patients (pts) gave written informed consent.

 

DA-EPOCH was given on Days 1-5 with G-CSF. Three dose levels (DL) of InO given on Days 8 and 15 were studied in 28-day cycles: DL1, 0.3 and 0.3 mg/m2; DL2, 0.6 and 0.3 mg/m2; and DL3, 0.6 and 0.6 mg/m2 (respectively). In Cycles 2+, EPOCH was dose-adjusted based on the hematologic nadir from the prior cycle. Up to 4 cycles were permitted. Hepatic prophylaxis with ursodiol and CNS-directed therapy with intrathecal chemotherapy was recommended.

 

MTD was the dose of InO yielding a true dose-limiting toxicity (DLT) rate of 33%. Initial dose-escalation plan for InO was a 6+6 design, but after 5 pts enrolled, this was modified to Bayesian Optimal Interval Design (BOIN) with target accrual of 24 pts. Secondary objectives were descriptions of treatment-related adverse events (TRAEs) per NCI CTCAE v5; efficacy by rate of complete remission without or with incomplete hematologic recovery (CR/CRi) and response at EMD sites per NCCN; measurable residual disease negativity (MRD-) by multiparameter flow cytometry (MFC) and high-throughput sequencing (HTS; clonoSEQ) of bone marrow aspirate; and survival.

Results
To date, 17 pts have been enrolled (Table). All are evaluable for DLT. 5 pts were treated at DL1; then per BOIN, 3 pts at DL2, and 9 pts at DL3. Median number of cycles given was 2 (range, 1-3). There have been 4 DLTs: 1 at DL2 (20%; grade 4 sepsis) and 3 at DL3 (33%; grade 4 hyponatremia, grade 4 SOS, and prolonged pancytopenia). The single case (6%) of SOS occurred after allografting and is ongoing. There have been no treatment-related deaths. Grade 3+ non-heme TRAEs were seen in 13 pts (76%). Those seen in >1 pt were infections (5 pts; 8 events), neutropenic fever (5 pts; 5 events), oral mucositis (3 pts; 4 events), and increased ALT (2 pts; 3 events); all these events resolved. Other hepatic toxicity was generally mild. Of 10 pts who received ≥2 cycles, 5 (50%) escalated the dosing of EPOCH, while 2 (20%) de-escalated.

 

17 pts are evaluable for response. Of 13 with >5% blasts, 12 (92%; 90% confidence interval 68-100%) achieved CR/CRi, 10 (77%) after 1 cycle. MRD- by MFC was achieved in 9 (75%); 1 had prior InO. In the 5 pts with EMD, 4 (80%) responded including 3 CRs. To date, 6 pts (35%) have undergone allograft post-study. Median follow-up of survivors is 7 mo, with 7 pts in ongoing remission beyond 6 mo.

Conclusion
DA-EPOCH-InO has a manageable toxicity profile with infrequent DLTs and only 1 case of SOS in heavily pre-treated adults with B-ALL. Nearly all pts with >5% blasts at enrollment achieved CR, with most being MRD- by MFC. Responses in EMD were common. Enrollment is ongoing. Updated follow-up and responses by HTS will be presented.

Keyword(s): Acute lymphoblastic leukemia, Antibody targeting, Chemotherapy, Clinical trial

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P351

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Clinical

Background
Despite new drugs, survival with R/R B-ALL remains poor. Combination therapies may improve outcomes, but none are proven superior, and toxicities may pose limits. InO has been added to low-intensity chemotherapy, but the risks/benefits of such combinations are poorly defined. As we recently found DA-EPOCH to be effective for untreated ALL, we here tested the addition of InO to DA-EPOCH (#NCT03991884).

 

Aims
The primary objective was to estimate the maximum tolerated dose (MTD) of InO when added to DA-EPOCH.

 

Methods
Eligible adults had R/R CD22+ B-ALL with ≥5% blasts in blood/marrow or ≥1 site of extramedullary disease [EMD] ≥1.5 cm in diameter. No history of sinusoidal obstructive syndrome (SOS) or chronic liver disease was allowed. Other key eligibility criteria included bilirubin ≤1.5x upper limit of normal (ULN), AST/ALT ≤2.5x ULN, creatinine ≤1.5x ULN, QTc ≤500 msec, and ECOG 0-2. All patients (pts) gave written informed consent.

 

DA-EPOCH was given on Days 1-5 with G-CSF. Three dose levels (DL) of InO given on Days 8 and 15 were studied in 28-day cycles: DL1, 0.3 and 0.3 mg/m2; DL2, 0.6 and 0.3 mg/m2; and DL3, 0.6 and 0.6 mg/m2 (respectively). In Cycles 2+, EPOCH was dose-adjusted based on the hematologic nadir from the prior cycle. Up to 4 cycles were permitted. Hepatic prophylaxis with ursodiol and CNS-directed therapy with intrathecal chemotherapy was recommended.

 

MTD was the dose of InO yielding a true dose-limiting toxicity (DLT) rate of 33%. Initial dose-escalation plan for InO was a 6+6 design, but after 5 pts enrolled, this was modified to Bayesian Optimal Interval Design (BOIN) with target accrual of 24 pts. Secondary objectives were descriptions of treatment-related adverse events (TRAEs) per NCI CTCAE v5; efficacy by rate of complete remission without or with incomplete hematologic recovery (CR/CRi) and response at EMD sites per NCCN; measurable residual disease negativity (MRD-) by multiparameter flow cytometry (MFC) and high-throughput sequencing (HTS; clonoSEQ) of bone marrow aspirate; and survival.

Results
To date, 17 pts have been enrolled (Table). All are evaluable for DLT. 5 pts were treated at DL1; then per BOIN, 3 pts at DL2, and 9 pts at DL3. Median number of cycles given was 2 (range, 1-3). There have been 4 DLTs: 1 at DL2 (20%; grade 4 sepsis) and 3 at DL3 (33%; grade 4 hyponatremia, grade 4 SOS, and prolonged pancytopenia). The single case (6%) of SOS occurred after allografting and is ongoing. There have been no treatment-related deaths. Grade 3+ non-heme TRAEs were seen in 13 pts (76%). Those seen in >1 pt were infections (5 pts; 8 events), neutropenic fever (5 pts; 5 events), oral mucositis (3 pts; 4 events), and increased ALT (2 pts; 3 events); all these events resolved. Other hepatic toxicity was generally mild. Of 10 pts who received ≥2 cycles, 5 (50%) escalated the dosing of EPOCH, while 2 (20%) de-escalated.

 

17 pts are evaluable for response. Of 13 with >5% blasts, 12 (92%; 90% confidence interval 68-100%) achieved CR/CRi, 10 (77%) after 1 cycle. MRD- by MFC was achieved in 9 (75%); 1 had prior InO. In the 5 pts with EMD, 4 (80%) responded including 3 CRs. To date, 6 pts (35%) have undergone allograft post-study. Median follow-up of survivors is 7 mo, with 7 pts in ongoing remission beyond 6 mo.

Conclusion
DA-EPOCH-InO has a manageable toxicity profile with infrequent DLTs and only 1 case of SOS in heavily pre-treated adults with B-ALL. Nearly all pts with >5% blasts at enrollment achieved CR, with most being MRD- by MFC. Responses in EMD were common. Enrollment is ongoing. Updated follow-up and responses by HTS will be presented.

Keyword(s): Acute lymphoblastic leukemia, Antibody targeting, Chemotherapy, Clinical trial

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