Blinatumomab is a bispecific T cell engager that has shown efficacy in relapsed/refractory Philadelphia chromosome (Ph)-positive and Ph-negative acute lymphoblastic leukemia (ALL). Considering its ...favorable safety and activity in advanced ALL, blinatumomab as a targeted immunotherapy is fast gaining a frontline position in the ALL treatment paradigm. There have been multiple completed and ongoing studies showing significant promise with improved response rates and survival outcomes and decreased treatment toxicity and need for multi-agent chemotherapy regimens. The early use of blinatumomab has established success in Ph-negative and Ph-positive B-ALL, and this has extended to older adults with ALL who have historically had substantially inferior outcomes compared to their pediatric and young adult counterparts. Herein we will review the current data describing the early use of blinatumomab in newly diagnosed adults with B-cell ALL and future directions.
We retrospectively analyzed 65 patients with refractory/relapsed (r/r) ALL who were treated with blinatumomab for predictors of leukemia response as well as clinical patterns of relapse and ...resistance with particular focus on downregulation of CD19 expression and extramedullary disease (EM‐ALL). The complete remission (CR) rate was 51%, and 15 (45%) responders underwent allogeneic hematopoietic cell transplantation (HCT) in CR. High leukemia burden (bone marrow blasts >50%) (P = .02), history of prior EM‐ALL (P = .005), and active EM‐ALL at the time of initiating blinatumomab (P = .05) predicted lower CR rate. Among refractory cases, 13 (41%) had evidence of EM‐ALL progression, and CD19 expression was negative or dim in 18% and 23%, respectively. Among responders, 20 (61%) subsequently relapsed among whom EM‐ALL relapse occurred in 8 (40%) patients, and CD19 expression was negative or dim in 35 and 6% of evaluable cases, respectively. Pretreatment moderate/strong CD19 expression (P = .01) and history of prior EM‐ALL during ALL course (P = .04) were risk factors for developing EM‐ALL at progression/relapse. However, no pretreatment factors predicted progression/relapse with CD19‐negative ALL. Overall‐survival (OS) and even‐free survival were improved for patients underwent allogeneic HCT compared to responders who did not. Furthermore, OS was superior for patients responded to blinatumomab compared to those who did not. Extramedullary and CD19‐negative disease are common during blinatumomab failure in r/r ALL. In addition to high leukemia burden, concurrent or prior history EM‐ALL were associated with lower response to blinatumomab. Higher CD19 expression as well as prior history of EM‐ALL were associated with EM‐ALL at the time of blinatumomab failure.
Although pediatric acute lymphoblastic leukemia (ALL) has cure rates of over 90%, adult ALL remains a challenging disease to treat, with cure rates roughly half those seen in children. The inferior ...outcomes in adults can be attributed mainly to adverse genetic features, as well as the inability-particularly of older adults-to tolerate chemotherapy. Modest improvements have been seen in outcomes for adolescents and young adults; these can largely be attributed to the use of pediatric-type combination chemotherapy regimens in patients aged 50 years or younger. In patients with Philadelphia chromosome-positive ALL, once a very-high-risk group, outcomes have markedly improved as a result of the use of tyrosine kinase inhibitors in combination with chemotherapy. The persistence of minimal residual disease has emerged as the single most important prognostic factor for ALL and is increasingly being used to help make decisions regarding allogeneic hematopoietic stem cell transplantation or novel salvage therapies. Relapsed/refractory ALL has had a dismal prognosis. In recent years, novel immune-based therapies have been developed that have shown impressive results and that have the potential to improve the outcome of relapsed ALL. These include antibody-drug conjugates, the bispecific T-cell-engaging antibody blinatumomab, and chimeric antigen receptor-modified T cells.
Venetoclax in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) has demonstrated exceptional activity in elderly and unfit patients with newly diagnosed acute myeloid ...leukemia (AML). Notably, the safety profile of venetoclax-based induction regimens was favorable, with a low rate of early treatment-related mortality, even in frail study participants. Thus, the introduction of venetoclax has transformed the landscape of AML therapy in elderly patients. Given these promising results, venetoclax in combination with other agents is now being studied as a frontline therapy in younger patients with AML, as well as in relapsed/refractory AML patients. Here, we review clinical data for venetoclax-based therapy in AML, both from prospective as well as retrospective studies, and highlight ongoing novel studies of venetoclax-containing regimens and discuss future research directions.
Opinion statement
Acute lymphoblastic leukemia (ALL) in adults is associated with poor outcomes as compared to children when treated with chemotherapy, leading to a considerably inferior cure rate. ...Historically, consolidation with allogeneic hematopoietic cell transplant (alloHCT) was routinely recommended for eligible adults with ALL in first complete remission (CR1) if a donor was available, since randomized studies showed superiority over continuing chemotherapy. With the increasing use of pediatric-inspired frontline regimens in young adults with ALL and the availability of novel salvage agents for relapsed/refractory B-cell ALL that have high potential in inducing a second CR, the role of early alloHCT in the treatment paradigm for ALL needs to be reevaluated, and the decision should be individualized for each patient. Simultaneously, alloHCT has evolved considerably lately, and historical randomized studies that have proven the benefit of alloHCT in adults with ALL in CR1 did not included the increasing use of reduced intensity conditioning and haploidentical transplants, and therefore, data may not entirely apply. Nowadays, detectable minimal residual disease (MRD) is the most prognostic determinant of ALL outcome and should be a major consideration in the decision to perform alloHcT in CR1. Nonetheless, other biological and clinical factors remain relevant and can support the complex decision-making. Such factors include high-risk leukemia genetics, the type of administered chemotherapy regimen and the ability of the patient to tolerate all key components of the regimen, and the availability of effective salvage therapies that allow alloHCT to be performed in CR2 in case of relapse after chemotherapy.
Summary
Studies of ethnic disparities in malignancies have revealed variation in clinical outcomes. In multiple myeloma (MM), previous literature has focused only on patients of Caucasian and ...African‐American (AA) descent. We present a Surveillance Epidemiology and End Results (SEER)‐based outcome analysis of MM patients from a broader range of ethnicities, representing current United States demographics. The SEER 17 Registry data was utilized to analyse adult MM patients diagnosed since 1992 (n = 37 963), as patients of other ethnicities were not well represented prior to that. Overall survival (OS) and myeloma‐specific survival (MSS) were compared across different ethnicities stratified by year of diagnosis, registry identification, age, sex and marital‐status. Hispanics had the youngest median age at diagnosis (65 years) and Whites had the oldest (71 years) (P < 0·001). Increased age at diagnosis was an independent predictor of decreased OS and MSS. Asians had the best median OS (2·7 years) and MSS (4·1 years), while Hispanics had the worst median OS (2·4 years). These trends were more pronounced in patients ≥75 years. Cumulative survival benefit over successive years was largest among Whites (1·3 years) and smallest among Asians (0·5 years). These disparities may be secondary to multifactorial causes that need to be explored and should be considered for optimal triaging of healthcare resources.
Administering asparaginase has always been problematic in adults because most general oncologists who treat adults are not familiar with its usage and toxicity. The toxicity profile of the drug is ...unique and is not observed with any other chemotherapy agent. Furthermore, asparaginase is almost exclusively used in acute lymphoblastic leukemia (ALL), which is a very rare cancer in adults. Currently, the long-acting pegylated form (pegasparaginase) is the only Escherichia coli–derived asparaginase available in the United States. The use of pediatric regimens is likely to lead to more adult patients receiving multiple doses of pegasparaginase. However, oncologists who treat adults may be reluctant to use pegasparaginase or may unnecessarily discontinue administering it because of certain adverse effects. As a result, the clinical benefit of multiple doses of pegasparaginase will be missed. Despite the fact that pegasparaginase is associated with unique toxicities, the majority are nonfatal, manageable, and reversible. Here, we describe real-life cases of adults with ALL who were treated with pediatric-inspired regimens that incorporated pegasparaginase to illustrate the management of several pegasparaginase-associated adverse effects and guide whether and how to continue the drug.
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Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent antitumor effects in B-cell malignancies including acute lymphoblastic leukemia (ALL), but antigen loss remains the major cause ...of treatment failure. To mitigate antigen escape and potentially improve the durability of remission, we developed a dual-targeting approach using an optimized, bispecific CAR construct that targets both CD19 and BAFF-R. CD19/BAFF-R dual CAR T cells exhibited antigen-specific cytokine release, degranulation, and cytotoxicity against both CD19-/- and BAFF-R-/- variant human ALL cells in vitro. Immunodeficient mice engrafted with mixed CD19-/- and BAFF-R-/- variant ALL cells and treated with a single dose of CD19/BAFF-R dual CAR T cells experienced complete eradication of both CD19-/- and BAFF-R-/- ALL variants, whereas mice treated with monospecific CD19 or BAFF-R CAR T cells succumbed to outgrowths of CD19-/BAFF-R+ or CD19+/BAFF-R- tumors, respectively. Further, CD19/BAFF-R dual CAR T cells showed prolonged in vivo persistence, raising the possibility that these cells may have the potential to promote durable remissions. Together, our data support clinical translation of BAFF-R/CD19 dual CAR T cells to treat ALL.
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