Bortezomib and rituximab in de novo adolescent/adult CD20-positive, Ph-negative pre-B-cell acute lymphoblastic leukemia

Abstract

The expression of CD20 in precursor B-cell ALL is associated with poor outcomes. The addition of rituximab to intensive chemotherapy in CD-20 positive ALL has led to improved outcomes in several studies. However, there is no clear evidence regarding the optimal number of doses and its benefit without an allogeneic stem cell transplant. Achieving measurable residual disease (MRD) negative status post-induction would reduce the requirement for a transplant. Novel approaches are needed to induce a higher proportion of MRD negative complete responses in patients with high-risk ALL. Given bortezomib's activity in relapsed ALL and its synergism with rituximab in B-cell lymphomas, the addition of bortezomib to rituximab and chemotherapy may provide an incremental benefit in CD20-positive-precursor B-cell ALL. We conducted a phase II study to test the activity of bortezomib and rituximab in combination with a pediatric-inspired regimen during induction therapy in newly diagnosed adolescents and adults (>14 years of age) with CD20-positive, Philadelphia (Ph)-negative precursor B- ALL, with bone marrow MRD negativity at the end of induction (EOI) as the primary endpoint. From December 2017 through August 2019, a total of 35 patients were enrolled. EOI-MRD-negative status was achieved in 70.99% of patients, as opposed to 51.7% in the historical cohort treated with chemotherapy alone. MRD negative rates improved to 87.5% post-consolidation. At a median follow-up of 21 months, the event-free survival and overall survival were 78.8% [95% CI - 66%- 94%] and 78.7% [95% CI - 65.8%- 94%], respectively. There was no significant increase in toxicity with bortezomib and rituximab compared to the historical cohort. The incidence of neuropathy was 26% (all less than grade 3). The combination of bortezomib, rituximab, and a pediatric-inspired ALL regimen is active and well-tolerated in de-novo CD20-positive Ph-negative precursor B-ALL. This trial is registered with the Clinical Trials Registry-India, CTRI/2017/04/008393.

Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas

“…No significant increase in the infection risk has been observed between de novo CD20+ pediatric patients with ALL treated with chemotherapy supplemented by rituximab, while the addition of bortezomib in the same population also seems to minimally affect the toxicity profile (2.9% with fatal infection; 67.6% with grade ≥3 infection; invasive fungal infections (IFDs) in 40% of episodes) [ 43 , 44 ]. In contrast, the addition of rituximab to a modified hyper-CVAD regimen for CD20+ pediatric patients with ALL was associated with a higher rate (9.2%) of fatal infections [ 45 ].…”

Bortezomib advanced mechanisms of action in multiple myeloma, solid and liquid tumors along with its novel therapeutic applications

“…Also, children and young adults with Early T-Cell Precursor (ETP) Acute Lymphoblastic Leukemia suffered from poor prognosis compared with other T-ALL subtypes. At this stage, Venetoclax was used as a sole therapy until resistance cases emerged (Jain et al, 2021[ 63 ]). Venetoclax was initiated individually with successful preliminary antitumor activity reaching resistant cases (Bose et al, 2017[ 16 ]).…”

Minimal Residual Disease in the Management of B-Cell Acute Lymphoblastic Leukemia: A Systematic Review of Studies from Indian Settings

“…Evaluating the expression of CD123 in acute leukemia, comparing it with post-induction morphologic complete remission and MRD status CD123 may be considered as a cardinal marker for: Residual disease assessment Response evaluation in AML and B-cell ALL Jain et al [24] 35…”

“…Regarding the timings for assessment, five studies followed EOI assessments on days 29-33 [22][23][24][25][26], except for studies by Chatterjee et al [32] and Das et al [33] that made assessments between days 35 and 40 and 30 and 35, respectively [27]. Individual studies (n = 2) that evaluated at midinduction on day 21 or after phase 1a induction were also identified [27,28].…”