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Blood Advances Feb 2022The molecular hallmark of childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent, prognostic genetic alterations, many of which are cryptic by... (Clinical Trial)
Clinical Trial
The molecular hallmark of childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent, prognostic genetic alterations, many of which are cryptic by conventional cytogenetics. RNA sequencing (RNA-seq) is a powerful next-generation sequencing technology that can simultaneously identify cryptic gene rearrangements, sequence mutations and gene expression profiles in a single assay. We examined the feasibility and utility of incorporating RNA-seq into a prospective multicenter phase 3 clinical trial for children with newly diagnosed ALL. The Dana-Farber Cancer Institute ALL Consortium Protocol 16-001 enrolled 173 patients with ALL who consented to optional studies and had samples available for RNA-seq. RNA-seq identified at least 1 alteration in 157 patients (91%). Fusion detection was 100% concordant with results obtained from conventional cytogenetic analyses. An additional 56 gene fusions were identified by RNA-seq, many of which confer prognostic or therapeutic significance. Gene expression profiling enabled further molecular classification into the following B-cell ALL (B-ALL) subgroups: high hyperdiploid (n = 36), ETV6-RUNX1/-like (n = 31), TCF3-PBX1 (n = 7), KMT2A-rearranged (KMT2A-R; n = 5), intrachromosomal amplification of chromosome 21 (iAMP21) (n = 1), hypodiploid (n = 1), Philadelphia chromosome (Ph)-positive/Ph-like (n = 16), DUX4-R (n = 11), PAX5 alterations (PAX5 alt; n = 11), PAX5 P80R (n = 1), ZNF384-R (n = 4), NUTM1-R (n = 1), MEF2D-R (n = 1), and others (n = 10). RNA-seq identified 141 nonsynonymous mutations in 93 patients (54%); the most frequent were RAS-MAPK pathway mutations. Among 79 patients with both low-density array and RNA-seq data for the Philadelphia chromosome-like gene signature prediction, results were concordant in 74 patients (94%). In conclusion, RNA-seq identified several clinically relevant genetic alterations not detected by conventional methods, which supports the integration of this technology into front-line pediatric ALL trials. This trial was registered at www.clinicaltrials.gov as #NCT03020030.
Topics: Child; Gene Expression Profiling; Gene Rearrangement; Humans; Multicenter Studies as Topic; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies
PubMed: 34933343
DOI: 10.1182/bloodadvances.2021005634 -
Blood Advances Jan 2022The standard treatment for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by... (Clinical Trial)
Clinical Trial
The standard treatment for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.
Topics: Acute Disease; Adult; Dasatinib; Humans; Imatinib Mesylate; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence
PubMed: 34516628
DOI: 10.1182/bloodadvances.2021004607 -
Journal of Clinical Oncology : Official... May 2022Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome-negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as...
SWOG 1318: A Phase II Trial of Blinatumomab Followed by POMP Maintenance in Older Patients With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.
PURPOSE
Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome-negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population.
PATIENTS AND METHODS
Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome-negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis.
RESULTS
Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively.
CONCLUSION
Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome-negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored.
Topics: Aged; Antibodies, Bispecific; Antineoplastic Combined Chemotherapy Protocols; Humans; Lymphoma, B-Cell; Methotrexate; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 35157496
DOI: 10.1200/JCO.21.01766 -
JAMA Jun 2024In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I.
OBJECTIVE
To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL.
DESIGN, SETTING, AND PARTICIPANTS
Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022.
INTERVENTION
Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission.
MAIN OUTCOMES AND MEASURES
The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival.
RESULTS
Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%).
CONCLUSIONS AND RELEVANCE
Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03589326.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Young Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Fusion Proteins, bcr-abl; Imatinib Mesylate; Imidazoles; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Progression-Free Survival; Protein Kinase Inhibitors; Pyridazines; Remission Induction; Adolescent
PubMed: 38722621
DOI: 10.1001/jama.2024.4783 -
JAMA Oncology Mar 2020A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).
OBJECTIVE
To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation.
DESIGN, SETTING, AND PARTICIPANTS
This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019.
INTERVENTIONS
Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy.
MAIN OUTCOMES AND MEASURES
The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival.
RESULTS
Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups.
CONCLUSIONS AND RELEVANCE
Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation.
TRIAL REGISTRATION
Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.
Topics: Antineoplastic Agents; Child; Child, Preschool; Dasatinib; Female; Humans; Imatinib Mesylate; Infant; Male; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Treatment Outcome
PubMed: 31944221
DOI: 10.1001/jamaoncol.2019.5868 -
Journal of Clinical Oncology : Official... Mar 2024We tested whether blinatumomab (Blina) is effective as a toxicity-sparing alternative to first-line intensive chemotherapy in children and young persons (CYP) with B-ALL...
PURPOSE
We tested whether blinatumomab (Blina) is effective as a toxicity-sparing alternative to first-line intensive chemotherapy in children and young persons (CYP) with B-ALL who were chemotherapy-intolerant or chemotherapy-resistant.
METHODS
Data were collected for consecutive CYP (age 1-24 years) with Philadelphia chromosome-positive or Philadelphia chromosome-negative B-ALL who received Blina as first-line therapy. Blina was given as replacement for postremission intensive chemotherapy to patients with chemotherapy intolerance or resistance. Blina responders received further chemotherapy (Blin-CT) or first remission hematopoietic stem-cell transplant (Blin-HSCT) if indicated. Event-free survival (EFS) and overall survival (OS) of the Blin-CT group were compared with those of matched controls treated with standard chemotherapy in the UKALL 2003 trial. Events were defined as death, relapse, or secondary cancer.
RESULTS
From February 2018 to February 2023, 105 patients were treated, of whom 85 were in the Blin-CT group and 20 were in the Blin-HSCT group. A majority of Blin-CT patients received Blina for chemotherapy intolerance (70 of 85, 82%), and the group had a higher-risk profile than unselected patients with B-ALL. Blina was well tolerated with only one patient having a grade 3/4-related toxicity event, and of the 60 patients who were minimal residual disease-positive pre-Blina, 58 of 60 (97%) responded. At a median follow-up of 22 months, the 2-year outcomes of the 80 matched Blin-CT group patients were similar to those of 192 controls (EFS, 95% [95% CI, 85 to 98] 90% [95% CI, 65 to 93] and OS, 97% [95% CI, 86 to 99] 94% [95% CI, 89 to 96]). Of the 20 in the HSCT group, three died because of transplant complications and two relapsed.
CONCLUSION
Blina is safe and effective in first-line treatment of chemotherapy-intolerant CYP with ALL.
Topics: Child; Humans; Infant; Child, Preschool; Adolescent; Young Adult; Adult; Philadelphia Chromosome; Neoplasm Recurrence, Local; Antibodies, Bispecific; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation
PubMed: 37967307
DOI: 10.1200/JCO.23.01392 -
Journal of the National Comprehensive... Feb 2024Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that...
Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.
Topics: Humans; Blast Crisis; Protein Kinase Inhibitors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Leukemia, Myeloid, Chronic-Phase; Fusion Proteins, bcr-abl
PubMed: 38394770
DOI: 10.6004/jnccn.2024.0007 -
Cancer Jun 2021The outcome of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. The combination of inotuzumab with low-intensity mini-hyper-CVD...
Long-term follow-up of salvage therapy using a combination of inotuzumab ozogamicin and mini-hyper-CVD with or without blinatumomab in relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic leukemia.
BACKGROUND
The outcome of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. The combination of inotuzumab with low-intensity mini-hyper-CVD (mini-hyper-CVD; cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m × 4 doses) chemotherapy has shown encouraging results. The sequential addition of blinatumomab might improve outcome in patients with R/R ALL.
METHODS
We used lower intensity chemotherapy, mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m x 4 doses) compared to conventional hyper-CVAD.
RESULTS
Ninety-six patients with a median age of 37 years (range, 18-87 years) were treated. Overall, 77 patients (80%) responded, 55 (57%) of whom achieved complete response. The overall measurable residual disease negativity rate among responders was 83%. Forty-four (46%) patients underwent later allogeneic stem cell transplantation. Veno-occlusive disease of any grade occurred in 10 (10%) patients. The rates were 13% with the original schedule and 3% with the use of lower-dose inotuzumab and sequential blinatumomab. With a median follow-up of 36 months, the median overall survival (OS) was 13.4 months, with 3-year OS rates of 33%. The 3-year OS rate for patients with CD22 expression ≥70% and without adverse cytogenetics (KMT2A rearrangements, low hypodiploidy/near triploidy) was 55%.
CONCLUSION
The combination of inotuzumab and low-intensity mini-hyper-CVD chemotherapy with or without blinatumomab shows sustained efficacy in patients with R/R ALL.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Bispecific; Follow-Up Studies; Humans; Inotuzumab Ozogamicin; Middle Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Salvage Therapy; Young Adult
PubMed: 33740268
DOI: 10.1002/cncr.33469 -
European Journal of Cancer (Oxford,... Mar 2021To evaluate long-term durability of blinatumomab, a BiTE® (bispecific T-cell engager) molecule, in adults with relapsed/refractory (R/R) Philadelphia...
Long-term follow-up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukaemia: Final analysis of ALCANTARA study.
AIM
To evaluate long-term durability of blinatumomab, a BiTE® (bispecific T-cell engager) molecule, in adults with relapsed/refractory (R/R) Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukaemia (ALL).
METHODS
In this final analysis of an open-label, single-arm, phase 2, multicentre ALCANTARA study (NCT02000427), adults (age ≥18 years) with Ph+ ALL who had relapsed or were refractory to at least one TKI were included. The primary endpoint was the proportion of patients who achieved complete remission (CR)/CR with partial haematologic recovery (CRh) during the first two cycles of blinatumomab treatment.
RESULTS
The final analysis included 45 patients who completed the study between 3rd January 2014 and 6th January 2017, of which 16 (35.6%; 95% CI, 21.9%-51.2%) achieved CR/CRh within the first two blinatumomab cycles. After a median follow-up of 16.1 months, median relapse-free survival (RFS) was 6.8 (95% CI, 4.4-not estimable [NE]) months. Median overall survival (OS) was 9.0 (95% CI, 5.7-13.5) months with a median follow-up of 25.1 months. Median OS in patients with CR (19.8 [95% CI, 12.1-NE] months) was greater than in those without CR (6.0 [95% CI, 2.9-7.1] months). Of 16 patients with CR/CRh, 14 achieved complete minimal residual disease (MRD) response; the median duration of complete MRD response was 9.7 (95% CI, 5.2-NE) months. Treatment-related adverse events were consistent with those previously reported.
CONCLUSION
Long-term durability of responses to blinatumomab was demonstrated in patients with R/R Ph+ ALL.
Topics: Adult; Aged; Antibodies, Bispecific; Antineoplastic Agents; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Philadelphia Chromosome; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Salvage Therapy; Survival Rate; Young Adult
PubMed: 33588145
DOI: 10.1016/j.ejca.2020.12.022 -
Best Practice & Research. Clinical... Dec 2019Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subset of B-cell ALL with a spectrum of underlying genetic alterations that... (Review)
Review
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subset of B-cell ALL with a spectrum of underlying genetic alterations that activate kinase or cytokine receptor signaling. Ph-like ALL occurs at all ages but is most common in adolescents and young adults and is postulated to be a factor in the inferior outcomes in this age group. Ph-like ALL confers a poor prognosis with conventional chemotherapy and the pediatric and adult oncology communities are conducting trials utilizing molecularly targeted approaches. In parallel, the role of immunotherapy is being assessed for this unique and biologically diverse ALL subgroup.
Topics: Adolescent; Adult; Age Factors; Clinical Trials as Topic; Humans; Immunotherapy; Philadelphia Chromosome; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 31779971
DOI: 10.1016/j.beha.2019.101096