Jan A. Burger

Inotuzumab ozogamicin, an anti-CD22 antibody-drug conjugate, has demonstrated high response rates and measurable residual disease (MRD)-negativity in acute lymphoblastic leukemia (ALL). This phase 2 single-center study evaluated inotuzumab 0.6 mg/m² day 1 and 0.3 mg/m² day 8 (cycle 1) followed by 0.3 mg/m² days 1 and 8 (cycles 2-6) for adults with B-cell ALL in morphologic remission with detectable MRD (≥1 × 10^-4 by multiparameter flow cytometry, BCR::ABL1 transcripts ≥0.01% by polymerase chain reaction [PCR], or ≥1 × 10^-6 by next-generation sequencing [NGS]). Thirty-seven patients (median age 49 years) were treated, including 17 with Philadelphia-chromosome (Ph)-negative ALL and 20 with Ph-positive ALL. Twenty-eight patients (76%) were in first remission (CR1). Overall, 26 patients (70%) achieved MRD-negativity, including 76% of patients with Ph-negative ALL and 65% of patients with Ph-positive ALL. The NGS MRD-negativity rate was 73%. With a median follow-up of 50 months, the median overall survival (OS) was 61 months, with a median relapse-free survival (RFS) of 40 months. Patients treated in CR1 vs CR2+ had a median OS that was not reached versus 14 months, respectively (p = 0.056). Three cases (8%) of non-fatal sinusoidal obstructive syndrome (SOS) were observed. Inotuzumab was safe and effective at eradicating MRD.

We performed next-generation sequencing (NGS)-based measurable residual disease (MRD) assessment in 17 patients with chronic lymphocytic leukemia (CLL) in

Supplementary Appendix: Inclusion Criteria, Exclusion Criteria

Table S1a: Representativeness of study participants. Table S1b: Response and MRD rates at 12 and 24 cycles of combination treatment in intention-to-treat population (N=79). Table S2: Response and MRD rates at 12 and 24 cycles of combination treatment in evaluable patients. Table S3a: Univariate analysis of factors associated with CR/CRi at the end of treatment. Table S3b: Multivariate analysis of factors associated with CR/CRi at the end of treatment. Table S3c: Univariate analysis of factors associated with the best CR/CRi response. Table S3d: Multivariate analysis of factors associated with the best CR/CRi response. Table S4a: Univariate analysis of factors associated with marrow UMRD4 at the end of treatment. Table S4b: Multivariate analysis of factors associated with marrow UMRD4 at the end of treatment. Table S4c: Univariate analysis of factors associated with the best marrow UMRD4 response. Table S4d: Multivariate analysis of factors associated with the best marrow UMRD4 response. Table S5a: Univariate analysis of factors associated with progression-free survival. Table S5b: Multivariate analysis of factors associated with progression-free survival. Table S6: Summary of dose modifications. Table S7: The common reasons for dose reductions and dose interruptions. Table S8a: Summary of patients with U-MRD4 at EOT who had CLL progression. Table S8b: Summary of patients with MRD at EOT who had CLL progression.

Figures S1a: Response rates at serial time points in evaluable patients. Histogram showing iwCLL 2018 response at serial study time points in evaluable patients. CR/CRi rate was 64% at the end of cycle 12 and 77% at the end of cycle 24 of combination therapy. The best CR/CRi rate was 71% at anytime during the study treatment Figure S1b: Marrow UMRD4 rates in evaluable patients. Histogram showing bone marrow UMRD4 rates at serial study time points in evaluable patients. Bone marrow UMRD4 rate was 48% at the end of cycle 12 and 71% at the end of cycle 24 of combination therapy. The best bone marrow UMRD4 rate was 64% at anytime during the study treatment. Figure S2: Time to First Bone Marrow UMRD4. Reversed Kaplan-Meier survival estimate curve for time to first bone marrow UMRD4. The analysis included all patients who had MRD assessments after 3 months of combination therapy. Figure S3: Progression-free survival and overall survival stratified by IGHV mutation status (n=76). Kaplan-Meier progression-free and overall survival estimate curves stratified by IGHV mutation status. Log-rank test was used to compare between IGHV mutated and unmutated subgroups. Figure S4: Progression-free survival and overall survival in stratified by prior chemoimmunotherapy treatment. Kaplan-Meier progression-free and overall survival estimate curves stratified by prior chemoimmunotherapy treatment status. Log-rank test was used to compare between the two subgroups. Figure S5a: Time to treatment discontinuation in all patients. Kaplan-Meier survival estimate curve for time to treatment discontinuation. Figure S5b: Time to treatment discontinuation, stratified by IGHV status. Kaplan-Meier survival estimate curve for time to treatment discontinuation stratified by IGHV mutation status. Log-rank test was used to compare between the two subgroups. Figure S5c: Time to treatment discontinuation, stratified by TP53 aberration. Kaplan-Meier survival estimate curve for time to treatment discontinuation stratified by TP53 aberration status. Log-rank test was used to compare between the two subgroups. Figure S5d: Time to treatment discontinuation, stratified by prior chemoimmunotherapy treatment. Kaplan-Meier survival estimate curve for time to treatment discontinuation stratified by prior chemoimmunotherapy treatment status. Log-rank test was used to compare between the two subgroups. Figure S6: Patient Disposition. Flowchart showing patient disposition. Figure S7: Time to MRD recurrence in peripheral blood. Reversed Kaplan-Meier survival estimate curve for time to MRD recurrence in peripheral blood. Figure S8: Time to next treatment. Kaplan-Meier survival estimate curve for time to next treatment.

We explored the efficacy of the combination of ibrutinib + venetoclax in patients with relapsed and/or refractory (R/R) chronic lymphocytic leukemia (CLL). This phase II study enrolled 80 patients between July 2016 and September 2018. Patients received ibrutinib for the first 3 cycles, followed by ibrutinib + venetoclax for 24 cycles. Of the 79 treated patients, the median age was 61 years (IQR, 56–69); 65 (65/76, 86%) had unmutated IGHV and 29 (37%) had either del(17p) or a TP53 mutation. The median number of prior treatments was 1 (range, 1–3). The primary endpoint, best complete remission (CR) and CR with incomplete count recovery (CRi), was 67%, with a bone marrow undetectable measurable residual disease [10−4 sensitivity (U-MRD4)] rate of 61%. At 95.5 months of median follow-up, the estimated 7-year progression-free survival rate was 63.3%. Grade ≥3 neutropenia and thrombocytopenia occurred in 38% and 13% of patients, respectively. The 24-cycle ibrutinib + venetoclax combination led to high rates of CR/CRi and bone marrow U-MRD4 in patients with R/R CLL. Significance: The 24-cycle ibrutinib + venetoclax combination led to high rates of CR/CRi and bone marrow U-MRD4 in patients with R/R CLL. Responses were durable, including in patients with high-risk genomics.

Study population representation table