-
The Lancet. Haematology Dec 2022Blinatumomab is effective in relapsed or refractory B-cell acute lymphocytic leukaemia and results in high rates of minimal residual disease negativity. We aimed to...
Hyper-CVAD and sequential blinatumomab for newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: a single-arm, single-centre, phase 2 trial.
BACKGROUND
Blinatumomab is effective in relapsed or refractory B-cell acute lymphocytic leukaemia and results in high rates of minimal residual disease negativity. We aimed to establish whether the incorporation of blinatumomab into front-line therapy for acute lymphocytic leukaemia could improve outcomes.
METHODS
We conducted a single-arm, phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 14 years or older with confirmed, newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphocytic leukaemia were eligible, including patients who had received up to one course of chemotherapy before enrolment. Patients received four cycles of intensive chemotherapy (hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone] alternating with high-dose methotrexate and cytarabine), followed by four cycles of blinatumomab consolidation (up to 28 μg/day by continuous intravenous infusion for 28 days, given every 42 days). Maintenance consisted of 15 cycles of alternating blocks of three cycles of POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) chemotherapy and one of blinatumomab. The primary endpoint was relapse-free survival evaluated in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02877303, and is still enrolling patients.
FINDINGS
Between Nov 14, 2016, and Aug 27, 2020, 38 patients with newly diagnosed B-cell acute lymphocytic leukaemia were treated (median age 37 years [IQR 29-45]; 26 [68%] male; 21 [55%] White, non-Hispanic). With a median follow-up of 37 months (IQR 28-49), estimated 3-year relapse-free survival was 73% (95% CI 56-85). No patients relapsed more than 2 years after the start of therapy. One (3%) patient developed transient grade 3 cytokine release syndrome, and four (11%) patients had a grade 3 blinatumomab-related neurological event. The most common non-haematological grade 3-4 adverse events were infections, which occurred in 14 (37%) of 38 patients during induction and in 27 (71%) of 38 patients during consolidation chemotherapy cycles. One (3%) patient discontinued therapy because of treatment-related neurotoxicity. There were two deaths-one due to infection and one due to respiratory failure-which were not considered treatment-related.
INTERPRETATION
Front-line sequential chemotherapy with blinatumomab resulted in encouraging long-term survival. Future randomised studies should evaluate the routine incorporation of blinatumomab in the treatment of patients with Ph-negative B-cell acute lymphocytic leukaemia.
FUNDING
Amgen.
Topics: Male; Humans; Adult; Female; Philadelphia Chromosome; Vincristine; Methotrexate; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 36279879
DOI: 10.1016/S2352-3026(22)00285-X -
Journal of the National Comprehensive... Oct 2020Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22...
Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;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. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.
Topics: Fusion Proteins, bcr-abl; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Medical Oncology; Philadelphia Chromosome; Translocation, Genetic
PubMed: 33022644
DOI: 10.6004/jnccn.2020.0047 -
American Journal of Hematology Mar 2023The combination of ponatinib, a third-generation BCR::ABL1 tyrosine kinase inhibitor, with hyper-CVAD chemotherapy resulted in high rates of complete molecular...
The combination of ponatinib, a third-generation BCR::ABL1 tyrosine kinase inhibitor, with hyper-CVAD chemotherapy resulted in high rates of complete molecular remissions and survival, without the need for stem cell transplantation (SCT) in most patients with Philadelphia chromosome(Ph)-positive acute lymphocytic leukemia (ALL). Confirming these results in a large cohort of patients with longer follow-up would establish this regimen as a new standard of care. Adults with newly diagnosed Ph-positive ALL were treated with the hyper-CVAD regimen. Ponatinib was added as 45 mg daily × 14 during induction, then 45 mg daily continuously (first 37 patients) or 30 mg daily continuously, with dose reduction to 15 mg daily upon achievement of a complete molecular response (CMR; absence of a detectable BCR::ABL1 transcript by quantitative reverse transcription polymerase-chain reaction at a sensitivity of 0.01%). Maintenance therapy consisted of daily ponatinib and vincristine-prednisone monthly for 2 years, followed by daily ponatinib indefinitely. Twelve intrathecal injections of cytarabine alternating with methotrexate were given as central nervous system prophylaxis. The trial is registered on clinicaltrials.gov with the identifier NCT01424982. Eighty-six patients were treated. Their median age was 46 years (range, 21-80). All 68 patients with active disease at the initiation of therapy achieved complete response (CR) The cumulative CMR rate was 86%. Twenty- patients (23%) underwent allogeneic SCT. With a median follow-up of 80 months (range, 16-129 months), the estimated 6-year event-free survival rate was 65% and the overall survival rate was 75%. There was no difference in outcome by performance of allogeneic SCT in first CR. Common grade 3-5 adverse events included infection (n = 80, 93%), increased liver transaminases (n = 26, 31%) and total bilirubin (n = 13, 15%), hypertension (n = 15, 17%), pancreatitis (n = 13, 15%), hemorrhage (n = 12, 13%), and skin rash (n = 9, 10%). Two ponatinib-related deaths from myocardial infarction (3%; at months 2.6 and 4.3, respectively; both in CR) in the first 37 patients treated led to the ponatinib dose-modifications mentioned earlier, with no further ponatinib-related deaths observed. The long-term results of ponatinib and hyper-CVAD continue to demonstrate excellent outcome results and acceptable safety data, indicating that this strategy is another standard of care approach in frontline Ph-positive ALL.
Topics: Adult; Humans; Middle Aged; Cyclophosphamide; Doxorubicin; Philadelphia Chromosome; Follow-Up Studies; Dexamethasone; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36600670
DOI: 10.1002/ajh.26816 -
Current Research in Translational... 2023Before the advent of tyrosine kinase inhibitors (TKI) the outcome of Philadelphia chromosome positive (Ph) acute lymphoblastic leukemia (ALL) was dismal. The TKI... (Review)
Review
Before the advent of tyrosine kinase inhibitors (TKI) the outcome of Philadelphia chromosome positive (Ph) acute lymphoblastic leukemia (ALL) was dismal. The TKI combination with induction regimens has greatly improved the long-term outcome of Ph ALL, specifically ponatinib a most potent TKI in combination with HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) chemotherapy has demonstrated 5 years overall survival up to 75%. Historically, allogeneic hematopoietic stem cell transplantation (allo-HSCT) used to be the only potential curative option, recent data suggest that patients who achieve complete molecular remission within 3 months of TKI based induction therapies can achieve comparable overall survival with or without allo-HSCT. Intensive cytotoxic chemotherapy may not be the desirable treatment option in elderly Ph ALL patients due to anticipated tolerance, recently in a phase II study, "chemotherapy free" combinations such as blinatumomab (bispecific anti-CD3 and anti-CD19 monoclonal antibody) with ponatinib in treatment naïve Ph ALL patients have shown a complete response rate of 95% and 2 years overall survival of 93%. In this review we have highlighted the evolving treatment landscape of Ph ALL and what to look for in future.
Topics: Humans; Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Agents; Cyclophosphamide; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic
PubMed: 37121211
DOI: 10.1016/j.retram.2023.103392 -
Blood Advances Sep 2022Promising results have been shown with the combination of ponatinib and chemotherapy in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+...
Promising results have been shown with the combination of ponatinib and chemotherapy in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The PONALFIL (Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia) trial combined ponatinib (30 mg/d) with standard induction and consolidation chemotherapy followed by allogeneic hematopoietic stem cell transplant (alloHSCT) in newly diagnosed Ph+ ALL patients aged 18 to 60 years. Ponatinib was only given pre-emptively after alloHSCT. Primary end points were hematologic and molecular response before alloHSCT and event-free survival (EFS), including molecular relapse as event. Thirty patients (median age, 49 years; range, 19-59 years) entered the trial. All exhibited hematologic response, and alloHSCT was performed in 26 patients (20 in complete molecular response and 6 in major molecular response). Only 1 patient died (of graft-versus-host disease), and 5 patients exhibited molecular relapse after alloHSCT. No tyrosine kinase inhibitor was given after HSCT in 18 of 26 patients. Twenty-nine patients are alive (median follow-up, 2.1 years; range, 0.2-4.0 years), with 3-year EFS and overall survival (OS) of 70% (95% confidence interval, 51-89) and 96% (95% confidence interval, 89-100), respectively. Comparison of the PONALFIL and the ALLPh08 (Chemotherapy and Imatinib in Young Adults With Acute Lymphoblastic Leukemia Ph [BCR-ABL] Positive; same schedule, using imatinib as the tyrosine kinase inhibitor) trials by propensity score showed significant improvement in OS for patients in PONALFIL (3-year OS, 96% vs 53%; P = .002). The most frequent grade 3 to 4 adverse events were hematologic (42%), infectious (17%), and hepatic (22%), with only one vascular occlusive event. The combination of chemotherapy with ponatinib followed by alloHSCT is well tolerated, with encouraging EFS in adults with newly diagnosed Ph+ ALL. Cross-trial comparison suggests improvement vs imatinib (clinicaltrials.gov identifier #NCT02776605).
Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Imatinib Mesylate; Imidazoles; Middle Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyridazines; Recurrence; Young Adult
PubMed: 35675590
DOI: 10.1182/bloodadvances.2022007764 -
Leukemia & Lymphoma Dec 2021
Topics: Fusion Proteins, bcr-abl; Humans; Imidazoles; Niacinamide; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyrazoles; Pyridazines
PubMed: 34405773
DOI: 10.1080/10428194.2021.1966787 -
The Lancet. Haematology Jun 2023The outcome of older patients with B-cell acute lymphocytic leukaemia is inferior to that in younger patients due to the adverse disease biology and their inability to...
Mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in the subgroup of older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: long-term results of an open-label phase 2 trial.
BACKGROUND
The outcome of older patients with B-cell acute lymphocytic leukaemia is inferior to that in younger patients due to the adverse disease biology and their inability to tolerate intensive therapy. We aimed to study the long-term outcomes of inotuzumab ozogamicin with or without blinatumomab in combination with low-intensity chemotherapy in these patients.
METHODS
For this open-label phase 2 trial, patients aged 60 years or older with newly diagnosed, Philadelphia-chromosome negative, B-cell acute lymphocytic leukaemia, and an ECOG performance status of 3 or lower were eligible. This study was conducted at the University of Texas MD Anderson Cancer Center. The induction chemotherapy consisted of mini-hyper-CVD and has been published before; inotuzumab ozogamicin was administered intravenously on day 3 of the first four cycles at a dose of 1·3-1·8 mg/m in cycle 1, followed by 1·0-1·3 mg/m in subsequent cycles (cycles 2-4). Maintenance therapy with dose-reduced POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) was given for 3 years. From patient 50 onwards, the study protocol was amended to fractionate inotuzumab ozogamicin to a maximum cumulative dose of 2·7 mg/m (0·9 mg/m during cycle 1 fractionated into 0·6 mg/m on day 2 and 0·3 mg/m on day 8 of cycle 1, and 0·6 mg/m in cycles 2-4 fractionated into 0·3 mg/m on day 2 and 0·3 mg/m on day 8) followed by blinatumomab for four cycles (cycles 5-8). POMP maintenance was shortened to 12 cycles with one cycle of blinatumomab administered by continuous infusion after every three cycles of POMP. The primary endpoint was progression-free survival and was analysed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov (NCT01371630) and the present data is from the newly diagnosed, older subgroup of patients treated on the phase 2 portion of this trial; the trial is still enrolling patients.
RESULTS
Between Nov 11, 2011, and March 31, 2022, 80 patients were enrolled and treated (32 female and 48 male patients; median age 68 years [IQR 63-72]), 31 of whom were treated after the protocol amendment. With a median follow-up of 92·8 months (IQR 8·8-67·4), the 2-year progression-free survival was 58·2% (95% CI 46·7-68·2) and 5-year progression-free survival was 44·0% (31·2-54·3). At a median follow-up of 104·4 months (IQR 6·6-89·2) for the patients treated before the protocol amendment and 29·7 months (8·8-41·0) for those treated after the protocol amendment, median progression-free survival did not differ significantly between the two groups (34·7 months [95% CI 15·0-68·3] vs 56·4 months [11·3-69·7]; p=0·77). The most common grade 3-4 events were thrombocytopenia in 62 (78%) patients and febrile neutropenia in 26 (32%) patients. Six (8%) patients developed hepatic sinusoidal obstruction syndrome. There were eight (10%) deaths due to infectious complications, nine (11%) from complications related to secondary myeloid malignancy, and four (5%) from sinusoidal obstruction syndrome.
INTERPRETATION
Inotuzumab ozogamicin with or without blinatumomab added to low-intensity chemotherapy showed promising activity in terms of progression-free survival in older patients with B-cell acute lymphocytic leukaemia. Further attenuation of the chemotherapy regimen might improve tolerability while maintaining efficacy in older patients.
FUNDING
Pfizer and Amgen.
Topics: Humans; Male; Female; Aged; Inotuzumab Ozogamicin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hepatic Veno-Occlusive Disease; Philadelphia Chromosome; Leukemia, Lymphocytic, Chronic, B-Cell; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37187201
DOI: 10.1016/S2352-3026(23)00073-X -
Biology of Blood and Marrow... Mar 2020Relapse after stem cell transplantation for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) remains a significant challenge. In this systematic... (Review)
Review
Relapse after stem cell transplantation for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) remains a significant challenge. In this systematic review, we compare survival outcomes of second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib with first-generation TKI imatinib when these agents are used after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Ph+ ALL. In addition, we review the literature on TKI use to prevent relapse in patients who proceed to allo-HSCT beyond first complete response (>CR1). We performed database searches (inception to January 2018) using PubMed, Cochrane Library, and Embase. After exclusions, 17 articles were included in this analysis. Imatinib was used post-transplant either prophylactically or preemptively in 12 studies, 7 prospective studies and 5 retrospective studies. Overall survival (OS) for most prospective studies at 1.5 to 3 and 5 years ranged between 62% to 92% and 74.5% to 86.7%. Disease-free survival at 1.5 to 5 years was 60.4% to 92%. Additionally, imatinib failed to show survival benefit in patients who were >CR1 at the time of allo-HSCT. The cumulative OS for most retrospective studies using imatinib at 1 to 2 and 3 to 5 years was 42% to 100% and 33% to 40% respectively. Event-free survival at 1 to 2 and 3 to 5 years was 33.3% to 67% and 20% to 31% respectively. Dasatinib was used as maintenance treatment in 3 retrospective studies (n = 34). The OS for patients with Ph+ ALL using dasatinib as maintenance regimen after allo-HSCT at 1.4 to 3 years was 87% to 100% and disease-free survival at 1.4 to 3 years was 89% to 100%. Ninety-three percent of patients with minimal residual disease (MRD) positive status after allo-HSCT became MRD negative. Three prospective studies used nilotinib. In 2 studies where investigators studied patients with advanced chronic myeloid leukemia and Ph+ ALL, the cumulative OS and event-free survival at 7.5 months to 2 years were 69% to 84% and 56% to 84%, respectively. In the third study (n = 5) in patients with Ph+ ALL, nilotinib use resulted in OS at 5 years of 60%. Our review showed that use of TKIs (all generations) after allo-HSCT for patients in CR1 improved OS when given as a prophylactic or preemptive regimen. Limited data suggest that second-generation TKIs (ie, dasatinib) have a better OS, especially in patients with MRD-positive status. Imatinib did not improve OS in patients who were >CR1 at the time of allo-HSCT; for this population, no data were available with newer generation TKIs. The evaluation of survival benefit with newer generation TKIs and their efficacy in patients in >CR1 needs further study in large randomized clinical trials.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Protein Kinase Inhibitors; Retrospective Studies; Secondary Prevention; Transplantation, Homologous
PubMed: 31557532
DOI: 10.1016/j.bbmt.2019.09.022 -
Journal of Hematology & Oncology Jun 2020Recent years have witnessed major advances that have improved outcome of adults with acute lymphoblastic leukemia (ALL). The emergence of the concept of measurable... (Review)
Review
Recent years have witnessed major advances that have improved outcome of adults with acute lymphoblastic leukemia (ALL). The emergence of the concept of measurable residual disease has fine-tuned our prognostic models and guided our treatment decisions. The treatment paradigms of ALL have been revolutionized with the advent of tyrosine kinase inhibitors targeting BCR-ABL1, monoclonal antibodies targeting CD20 (rituximab), antibody-drug conjugates targeting CD22 (inotuzumab ozogamicin), bispecific antibodies (blinatumomab), and CD19 chimeric antigen receptor T cell therapy (tisagenlecleucel). These highly effective new agents are allowing for novel approaches that reduce reliance on intensive cytotoxic chemotherapy and hematopoietic stem cell transplantation in first remission. This comprehensive review will focus on the recent advances and future directions in novel therapeutic strategies in adult ALL.
Topics: Adolescent; Adult; Age Factors; Aged; Antibodies, Bispecific; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Clinical Decision-Making; Clinical Trials as Topic; Drugs, Investigational; Forecasting; Fusion Proteins, bcr-abl; Hematopoietic Stem Cell Transplantation; Humans; Immunoconjugates; Immunotherapy, Adoptive; Inotuzumab Ozogamicin; Leukemic Infiltration; Middle Aged; Molecular Targeted Therapy; Neoplasm Proteins; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Receptors, Antigen, T-Cell; Therapies, Investigational; Young Adult
PubMed: 32503572
DOI: 10.1186/s13045-020-00905-2