Although acute lymphoblastic leukemia is curable in one third of adult patients, results vary greatly on account of different clinical, immunologic, and cytogenetic/genetic characteristics. These ...data, along with the kinetics of response to early treatment, help establish the individual risk class with considerable accuracy, and support risk-specific treatments that should warrant optimal results with as little as possible nonrelapse mortality. Modern first-line therapy consists of standard- and high-dose chemotherapy (increasingly inspired to pediatric principles), hematopoietic stem-cell transplantation, and new targeted therapy, all integrated with the analysis of prognostic factors and the study of subclinical residual disease for key therapeutic decisions. These changes are improving long-term outcome, which in ongoing studies is expected close to 50% or greater.
Blinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in ...patients with relapsed or refractory B-cell precursor ALL on the basis of single-group trials that showed efficacy and manageable toxic effects.
In this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard-of-care chemotherapy. The primary end point was overall survival.
Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval CI, 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group.
Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167 .).
The Philadelphia (Ph) chromosome, resulting from the t(9;22)(q34;q11) translocation, can be found in chronic myeloid leukemia (CML) as well as in a subset of acute lymphoblastic leukemias (ALL). The ...deregulated BCR-ABL1 tyrosine kinase encoded by the fusion gene resulting from the translocation is considered the pathogenetic driver and can be therapeutically targeted. In both CML and Ph-positive (Ph+) ALL, tyrosine kinase inhibitors (TKIs) have significantly improved outcomes. In the TKI era, testing for BCR-ABL1 transcript levels by real-time quantitative polymerase chain reaction (RQ-PCR) has become the gold standard to monitor patient response, anticipate relapse, and guide therapeutic decisions. In CML, key molecular response milestones have been defined that draw the ideal trajectory towards optimal long-term outcomes. Treatment discontinuation (treatment-free remission, TFR) has proven feasible in a proportion of patients, and clinical efforts are now focused on how to increase this proportion and how to best select TFR candidates. In Ph+ ALL, results of trials with second- and third-generation TKIs are challenging the role of intensive chemotherapy and even that of allogeneic stem cell transplantation. Additional weapons are offered by the recently introduced monoclonal antibodies. In patients harboring mutations in the BCR-ABL1 kinase domain, prompt therapeutic reassessment and individualization based on mutation status are important to regain response and prevent disease progression. Next-generation sequencing is likely to become a precious tool for mutation testing because of the greater sensitivity and the possibility to discriminate between compound and polyclonal mutations. In this review, we discuss the latest advances in treatment and monitoring of CML and Ph+ ALL and the issues that still need to be addressed to make the best use of the therapeutic armamentarium and molecular testing technologies currently at our disposal.
Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of ...treatment.
We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment.
Of the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an
deletion plus additional genetic aberrations (
or
,
, or both i.e.,
).
mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%).
A chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.).
Minimal (or 'measurable') residual disease in acute lymphoblastic leukemia appears to be a prognostic indicator, with potential value in informing individualized treatment decisions. Complete ...understanding of the strength of the association between minimal residual disease and long-term outcomes is, however, lacking. A systematic literature review and meta-analysis were performed to elucidate the clinical significance of minimal residual disease with respect to relapse-free survival and overall survival in precursor B-cell acute lymphoblastic leukemia. A total of 23 articles and abstracts, most published between 2012 and 2016, were identified for inclusion in the primary meta-analysis. Typically, patients were in their first complete remission at the time of minimal residual disease assessment; in two studies, all patients were in their second, or later, complete remission. The primary analysis revealed improved relapse-free survival across all studies for patients who achieved minimal residual disease negativity (random effects hazard ratio, 2.34; 95% confidence interval, 1.91-2.86). Improved overall survival for patients who achieved minimal residual disease negativity was also observed (hazard ratio, 2.19; 95% confidence interval, 1.63-2.94). There was no observed difference in the impact of minimal residual disease status in subgroups based on disease stage, minimal residual disease sensitivity threshold level, Philadelphia chromosome status, histological phenotype, risk group, minimal residual disease testing location, minimal residual disease timing after induction, or minimal residual disease detection method. Despite heterogeneity in study design and patient populations between the contributing studies, these data provide a compelling argument for minimal residual disease as a clinical tool for assessing prognosis and guiding treatment decisions in precursor B-cell acute lymphoblastic leukemia.
Acute lymphoblastic leukemia (ALL) is a disseminated malignancy of B- or T-lymphoblasts which imposes a rapid and accurate diagnostic process to support an optimal risk-oriented therapy and thus ...increase the curability rate. The need for a precise diagnostic algorithm is underlined by the awareness that both ALL therapy and related success rates may vary greatly between ALL subsets, from standard chemotherapy in patients with standard-risk ALL, to allotransplantation (SCT) and targeted therapy in high-risk patients and cases expressing suitable biological targets, respectively. This review summarizes how best to identify ALL and the most relevant ALL subsets.
Adults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a ...retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990-2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%-41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%-50%). One- and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%-5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612.
The outstanding therapeutic progress achieved with modern pediatric regimens in childhood acute lymphoblastic leukemia (ALL) led efforts to explore whether a similar treatment approach could be ...equally effective and safe in older patients, starting initially with older adolescents and young adults (AYA), variably defined in different studies by an age between 15–18 and 25–39 years. Several comparative and noncomparative trials of this type have been carried out during the last two decades, enrolling thousands of patients. Almost without exception, the new strategy improved patients’ outcomes compared with traditional adult treatments in B-lineage and T-lineage Philadelphia (Ph) chromosome-negative B-ALL, while the use of tyrosine kinase inhibitors (TKI) led to comparative progress in Ph+ ALL, a former high-risk subset more typically observed in older age groups. At present, highly effective pediatric-based regimens warrant 5-year survival rates of 60–70% in AYA patients. In view of these data, the same approach was progressively extended to older patients, improving the results up to 55 years of age. Issues of treatment compliance and drug-related toxicity have thus far prevented a comparable therapeutic advancement in patients aged >55 years. This critical review updates and summarizes with pertinent examples this global, positive therapeutic change, and examines how to promote further progress with new targeted therapies that include novel immuno-therapeutics and other agents developed against the many molecular dysfunctions detectable in various ALL subsets. Substantial progress is expected to occur soon, bringing AYA survival figures very close to that of children, and also to improve the outcome of ALL at all ages.
Purpose of Review
Lymphoblastic lymphoma (LBL) is a rare, highly aggressive non-Hodgkin lymphoma variant virtually indistinguishable from acute lymphoblastic leukemia (ALL). We review the ...advancements in diagnostics, staging, treatment, and response assessment.
Recent Findings
T-LBL displays a mediastinal mass with pleuro-pericardic effusions as key distinctive features and is far more frequent than B-LBL. LBL is exquisitely sensitive to ALL-type chemotherapy, achieving cure rates in the order of 70% in adults and even more in children. Positron-emission tomography, genetic risk classifications, and minimal disseminated/residual disease assays are increasingly used to detect occult sites of involvement and predict treatment outcome. Stem cell transplantation is effective and should be considered for very high-risk subsets and/or at salvage.
Summary
Although curable in the majority of patients, about 25–30% of adults with LBL patients experience resistance or relapse following first-line therapy. It is essential to identify these cases early on and to explore new modalities of precision medicine with targeted agents.
Clinical risk classification is inaccurate in predicting relapse in adult patients with acute lymphoblastic leukemia, sometimes resulting in patients receiving inappropriate chemotherapy or stem cell ...transplantation (SCT). We studied minimal residual disease (MRD) as a predictive factor for recurrence and as a decisional tool for postconsolidation maintenance (in MRDneg) or SCT (in MRDpos). MRD was tested at weeks 10, 16, and 22 using real-time quantitative polymerase chain reaction with 1 or more sensitive probes. Only patients with t(9;22) or t(4;11) were immediately eligible for allogeneic SCT. Of 280 registered patients (236 in remission), 34 underwent an early SCT, 60 suffered from relapse or severe toxicity, and 142 were evaluable for MRD at the end of consolidation. Of these, 58 were MRDneg, 54 MRDpos, and 30 were not assessable. Five-year overall survival/disease-free survival rates were 0.75/0.72 in the MRDneg group compared with 0.33/0.14 in MRDpos (P = .001), regardless of the clinical risk class. MRD was the most significant risk factor for relapse (hazard ratio, 5.22). MRD results at weeks 16 to 22 correlated strongly with the earlier time point (P = .001) using a level of 10−4 or higher to define persistent disease. MRD analysis during early postremission therapy improves risk definitions and bolsters risk-oriented strategies. ClinicalTrials.gov identifier: NCT00358072.