Novel agents in acute lymphoblastic leukemia: an expanding role for inotuzumab ozogamicin in patients with measurable residual disease

Jabbour et al. (1) reported the results of a phase 2 monocentric study using the calicheamicin-conjugated anti-CD22 antibody inotuzumab ozogamicin (InO) in adult patients with B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) in complete hematologic remission (CHR) but failure to measurable residual disease (MRD) response or MRD recurrence.

Today, the attainment of complete MRD response is considered the major goal in the treatment strategy of ALL, since MRD is the most powerful prognostic factor for predicting relapse risk and survival (2,3), and a negative MRD status before allogeneic hematopoietic cell transplant (alloHCT) is crucial for achieving long-term remission (4).

Currently, the bispecific T-cell engager anti-CD3/CD19 antibody blinatumomab is the only drug approved for treatment of MRD in patients with BCP ALL. This indication came from the international, open label, phase 2 study BLAST, which enrolled Philadelphia negative (Ph-neg) adult patients with CD19⁺ BCP ALL in CHR but MRD persistence or MRD relapse at a level ≥1×10⁻³ after at least 3 blocks of intensive chemotherapy (5). After one cycle of blinatumomab 78% of the 113 patients evaluable for the primary endpoint obtained a complete MRD response irrespective of age, MRD level at baseline and history of previous hematologic relapse: one patient was subsequently reclassified as non-responder, thus bringing the rate of responders down to 77% (6). Relapse-free survival (RFS) in responders was significantly better for patients in first CHR (5), and long-term follow-up analysis demonstrated an overall survival (OS) benefit for patients attaining complete MRD response after blinatumomab treatment (median OS not reached vs. 14.4 months, P=0.002) (6). Interestingly, patients in first CHR who achieved complete MRD response after blinatumomab had similar chances of maintaining long-term remission with or without a subsequent alloHCT, while patients in second or later CHR obtained more benefit from consolidation alloHCT (6).

Similar results were reported in real-world experience and in other clinical trials including patients with lower levels of baseline MRD and history of previous alloHCT (7-11). Overall, the rates of complete MRD response in these studies ranged from 73% to 89% (Table 1), except for the ongoing GMALL 08/2013 trial: in the first report, only 55% of patients failing to obtain molecular response after consolidation chemotherapy achieved complete MRD response with blinatumomab.

Similarly, in Philadelphia-positive (Ph-pos) patients the sequential treatment with dasatinib induction and blinatumomab consolidation led to remarkable rates of molecular response (81%), and OS (80.7% at a median follow-up of 53 months), without any chemotherapy and with limited use of alloHCT (13,14).

The recent study from Jabbour et al. adds an important piece of knowledge in the field of MRD treatment, since it is the first full report of activity and safety of InO in this setting (1). In this phase 2 study conducted at MD Anderson Cancer Center (MDACC), 26 patients in CHR and MRD ≥1×10⁻⁴ after ≥3 months of prior standard therapy received InO at 0.6 mg/m² on day 1 and 0.3 mg/m² on day 8 of cycle 1, then at 0.3 mg/m² on days 1 and 8 of subsequent cycles, up to a maximum of 6 cycles. Both patients with Ph-neg (38%) and Ph-pos (62%) ALL were enrolled. Of note, 50% of patients had previously received blinatumomab and 19% of patients had already been allografted. Ph-pos patients received concomitant tyrosine kinase inhibitor (TKI) therapy, represented by ponatinib in most cases. MRD negativity, defined as undetectable disease by multiparametric flow cytometry (MFC) in Ph-neg patients and as undetectable disease by MFC with the absence of quantifiable BCR::ABL1 transcripts or BCR::ABL1 level <0.01% in Ph-pos patients, was attained by 18 out of 26 patients (69%). Six of these 18 MRD responders underwent subsequent alloHCT. After a median follow-up of 24 months, the 2-year RFS and OS rates were 54% and 60%, respectively. Among MRD complete responders, 2-year OS was 67% and 90% in patients who received or not alloHCT as consolidation treatment, respectively. Two patients (8%) developed veno-occlusive disease (VOD): both were Ph-pos patients treated with concomitant ponatinib, suggesting caution in the use of this combination due to the risk of liver toxicity.

To my knowledge, only one other study is investigating the role of InO in the MRD setting: the ongoing academic GIMEMA ALL2418 trial (12). Similar to the study by Jabbour et al., both Ph-neg and Ph-pos patients were enrolled in first or subsequent CHR with detectable MRD after at least 3 months of treatment with TKIs or 2 cycles of intensive therapy. However, the scope of the Italian study was different, aiming to evaluating the efficacy of InO in achieving MRD negativity prior to any transplantation procedure. InO was administered at a dose of 0.5 mg/m² on days 1, 8 and 15 of each cycle for up to 2 cycles, followed by alloHCT or maintenance according to transplant eligibility. An interim analysis of the first 39 enrolled patients showed an MRD negativity rate of 35%, which was higher in Ph-neg than in Ph-pos patients (42% and 25%, respectively). The reason for the lower MRD response rate compared to the study by Jabbour et al. might lie in the lower number of InO cycles or in the different methods of MRD evaluation (i.e., highly sensitive molecular techniques in the Italian study vs. MFC with a sensitivity of 10⁻⁴ in the MDACC study).

There is also robust evidence of the efficacy of CD19-specific chimeric antigen receptor (CAR)-T cells in eradicating MRD. In a pivotal phase 1 trial at the Memorial Sloan Kettering Cancer Center, patients in CHR and detectable MRD before treatment with 19-28z CAR-T cells had a markedly superior duration of remission and survival, and a lower incidence of adverse events, compared to patients with ≥5% bone marrow blasts (BMB) or extramedullary disease (15). This finding was confirmed in a large real-world series of pediatric and young adult patients who received commercial tisagenlecleucel: patients with low pre-treatment disease burden (<5% BMB, no extramedullary or central nervous system disease) had higher rates of complete MRD response after treatment and superior event-free survival and OS (16). Better outcomes in subjects with lower leukemic burden at lymphodepletion were also observed in a real-world series of adult patients treated with commercial brexucabtagene autoleucel (17) and in a pivotal trial with the fast off-rate CD19 binding domain CAR-T product obecabtagene autoleucel (18). In a phase I study specifically designed for patients in CHR but MRD persistence or MRD relapse, treatment with bispecific anti-CD19/anti-CD22 CAR-T cells resulted in a 100% rate of MRD response (n=15) at day 28 after infusion, with very limited toxicity. The long-term results were particularly promising, since 2-year RFS and OS were 77% and 86%, respectively, in many cases without consolidation with subsequent alloHCT (19). The Cassiopeia study (NCT03876769) is another ongoing clinical trial of tisagenlecleucel in children and young adults with high-risk ALL in CHR but persistent MRD at the end of chemotherapy. However, none of the CAR-T products presently available are licensed for use in patients with ALL in CHR and MRD persistence or relapse, and the burden of toxicity of CAR-T cells (including adverse events), along with organizational structure and costs, makes their use less attractive in this setting.

Therefore, InO is a more practical candidate to serve as an additional and distinct strategy for MRD treatment, with the logistical advantage of requiring weekly administration often in an outpatient setting, whereas blinatumomab requires a 28-day continuous infusion per cycle with the need for hospitalization at least for 3 days in the first treatment cycle.

However, many questions remain unanswered and will have to be the subject of future research (20).

First, which is the optimal positioning of novel agents? Some recent studies incorporated blinatumomab in the context of frontline treatment, irrespective of MRD status. In the Italian GIMEMA LAL2317 trial, 149 adult Ph-neg BCP ALL (up to the age of 65 years) were treated with a pediatric-like chemotherapy regimen incorporating two cycles of blinatumomab: the rate of MRD negativity improved from 70% after 3 cycles of chemotherapy to 95% following the first cycle of blinatumomab, and 3-year OS and DFS rates were 71% and 65%, respectively, a figure that seems superior to the historic experience in adults (21). At MDACC, 38 patients were treated with sequential therapy comprising 4 cycles (instead of 8) of intensive chemotherapy HyperCVAD/MA followed by 4 cycles of blinatumomab and maintenance treatment alternating conventional low-dose POPM (6-mercaptopurine + vincristine, +methotrexate + prednisone) chemotherapy and 4 additional blinatumomab cycles: MRD complete response was attained by 97% of patients and 3-year OS and progression-free survival rates were 81% and 73%, respectively (22). In a large randomized trial of the ECOG-ACRIN Cancer Research Group, patients who attained MRD negativity after intensive chemotherapy were randomized to receive blinatumomab or not: patients who received the immunotherapy had a significant survival benefit compared to standard maintenance treatment (23); thus paving the way for the use of blinatumomab in first-line treatment of every BCP-ALL patient, similar to what has been happening for decades with the use of Rituximab in CD20⁺ B-cell lymphomas. The data to define an analogous universal role of InO as a backbone of the induction treatment are less solid, however, the addition of InO to standard frontline chemotherapy seems to be an interesting option in particular for older patients, as demonstrated by two recent trials conducted by the MDACC and the German Multicenter Study Group for Adult ALL (GMALL) (24,25).

Second, is there a difference in sensitivity between Ph-neg and Ph-pos patients to novel agents? Many studies have consistently replicated the results of BLAST trial (5), showing that around 80% of MRD positive Ph-neg patients reach a complete MRD response after 1 cycle of blinatumomab (8-10). Rates of complete molecular response in Ph-pos patients are lower, around 60% (13). For instance, in the MRD cohort of the NEUF study, the rates of complete MRD response in Ph-neg and Ph-pos patients were 91% and 59%, respectively (7). This difference may be ascribed to a different composition of immune system between Ph-neg and Ph-pos patients, or to immunomodulation driven by concomitant TKI therapy (26), or it may simply reflect the persistence of a BCR::ABL1 positive signal not driven by leukemic blasts (27). Interestingly, the results presented by Jabbour et al. confirm a higher rate of complete MRD response in Ph-neg compared to Ph-pos patients (80% vs. 62%, respectively).

Third, will the earlier use of novel agents alter the prognostic significance of MRD? Presently, a positive MRD status at the end of induction/consolidation chemotherapy is a marker of resistance and represents a high-risk feature that dictates alloHCT. The BLAST trial showed that Ph-neg patients treated in first CHR could be cured with blinatumomab without further treatments (6). Similarly, Ph-pos ALL seems to be no longer an absolute indication for frontline alloHCT, as demonstrated by the excellent outcomes of patients who had complete MRD response after dasatinib and blinatumomab in the D-ALBA trial (14). Understanding whether the use of InO in the MRD setting is associated with long-term remission without need for alloHCT is of utmost importance in order to determine the optimal treatment strategy, i.e., 6 cycles as proposed by Jabbour et al. (1) or 2 cycles to limit the risk of VOD as in the GIMEMA ALL2418 study (12).

Finally, the high costs of novel therapies need to be considered (28). At present, cost-utility analyses are available only for the setting of relapsed/refractory patients, with divergent evidence (29,30). The treatment of patients in CHR with limited disease burden is likely to induce higher rates of long-lasting remissions without the need for further treatments, thus increasing the value of novel agents that would justify their use even in resource-limited settings. The cost-utility comparison between blinatumomab and inotuzumab in MRD positive patients needs further data and longer follow-up.

In conclusion, blinatumomab still represents the preferred option for MRD clearance in patients with BCP ALL. However, the results of the study by Jabbour et al., alongside other emerging evidence, may expand treatment opportunities and suggest that InO may become an attractive strategy for treatment of MRD-positive disease in selected populations.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-58/coif). The author reported participation on Advisory Boards funded by Amgen, Pfizer, Novartis, Bristol Myers Squibb, Incyte, and Ascentage Pharma, outside from the present work. The author has no other conflicts of interest to declare.

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