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What is this summary about? This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck.How was the research done? The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL.What were the results? After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).
Subject(s)
Adenine , Drug Resistance, Neoplasm , Leukemia, Lymphocytic, Chronic, B-Cell , Piperidines , Protein Kinase Inhibitors , Pyrazoles , Pyrimidines , Humans , Piperidines/therapeutic use , Adenine/analogs & derivatives , Adenine/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Pyrimidines/therapeutic use , Pyrazoles/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Antineoplastic Agents/therapeutic use , Pyrazines/therapeutic use , Thiazoles/therapeutic use , Treatment OutcomeABSTRACT
The last decade has seen remarkable progress in our understanding of disease biology of chronic lymphocytic leukaemia (CLL) and the development of novel targeted therapies. Randomised clinical trials have reported improved progression-free survival and overall survival with targeted therapies compared with chemoimmunotherapy, and thereby the role of chemoimmunotherapy in todays' era for treatment of CLL is limited. Bruton tyrosine kinase (BTK) inhibitors, BCL2 inhibitors, and CD20 monoclonal antibodies have been established as appropriate therapy options for patients with CLL, both as the first-line treatment and in the treatment of relapsed or refractory CLL. Several ongoing phase 3 trials are exploring different combinations of targeted therapies, and the results of these trials might change the treatment framework in first-line treatment of CLL. Non-covalent BTK inhibitors, chimeric antigen receptor T-cell therapy, and other therapeutic strategies are being investigated in relapsed CLL. Some of the therapies used in relapsed CLL, such as non-covalent BTK inhibitors, are now being pursued in earlier lines of therapy, including first-line treatment of CLL.
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We report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event-free survival (EFS) or overall survival (OS). With a median follow-up of 7.8 years (range: 0.40-18.8), eight patients have experienced disease relapse (5.8%), 4/111 with newly diagnosed HCL (3·6%) and 4/10 with HCLv (40%) (p = 0.002). The 10-year EFS and OS rates were 86.7% and 91.1%, respectively. Grade 3 adverse events were observed in 28 participants (20·1%), mostly due to infections. Treatment of HCL with sequential cladribine followed by rituximab is associated with excellent efficacy and safety results both in the frontline and relapsed settings.
Subject(s)
Adenine , Adenine/analogs & derivatives , Leukemia, Lymphocytic, Chronic, B-Cell , Piperidines , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Adenine/therapeutic use , Piperidines/therapeutic use , Male , Pyrazoles/therapeutic use , Female , Pyrimidines/therapeutic use , Aged , Treatment Outcome , Middle AgedABSTRACT
INTRODUCTION: The therapeutic landscape for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved over the past decade with dramatically improved outcomes with the introduction of targeted therapies. This unfortunately has not been the case for Richter transformation (RT), the histologic transformation to a more aggressive lymphoma, most typically diffuse large B-cell lymphoma (DLBCL). As such, RT continues to be one of the most challenging complications of CLL/SLL. Historically, RT has a poor response to treatment, with a minority reaching complete remission (CR) and overall survival (OS) being less than a year. AREAS COVERED: The focus of this review is to discuss the effectiveness of commonly used regimens, and review existing data for emerging regimens being examined in ongoing clinical trials to improve prognosis and outcomes in patients with RT. Despite extensive efforts to optimize therapies for RT, there is still no generalized consensus on either first-line treatment regimens or regimens in the relapsed/refractory setting. RT continues to carry a high mortality rate without durable response to current therapeutic agents. EXPERT OPINION: Ongoing and future research may identify novel treatment approaches that will eventually improve outcomes for patients with RT. The optimal care for RT patients is a clinical trial, when feasible.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Lymphoma, Large B-Cell, Diffuse , Standard of Care , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, Large B-Cell, Diffuse/therapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Clinical Trials as Topic , Molecular Targeted Therapy , Treatment Outcome , Disease ManagementABSTRACT
ABSTRACT: The phase 3 INO-VATE trial demonstrated higher rates of remission, measurable residual disease negativity, and improved overall survival for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (InO) vs standard-of-care chemotherapy (SC). Here, we examined associations between genomic alterations and the efficacy of InO. Of 326 randomized patients, 91 (InO, n = 43; SC, n = 48) had samples evaluable for genomic analysis. The spectrum of gene fusions and other genomic alterations observed was comparable with prior studies of adult ALL. Responses to InO were observed in all leukemic subtypes, genomic alterations, and risk groups. Significantly higher rates of complete remission (CR)/CR with incomplete count recovery were observed with InO vs SC in patients with BCR::ABL1-like ALL (85.7% [6/7] vs 0% [0/5]; P = .0076), with TP53 alterations (100% [5/5] vs 12.5% [1/8]; P = .0047), and in the high-risk BCR::ABL1- (BCR::ABL1-like, low-hypodiploid, KMT2A-rearranged) group (83.3% [10/12] vs 10.5% [2/19]; P < .0001). This retrospective, exploratory analysis of the INO-VATE trial demonstrated potential for benefit with InO for patients with R/R ALL across leukemic subtypes, including BCR::ABL1-like ALL, and for those bearing diverse genomic alterations. Further confirmation of the efficacy of InO in patients with R/R ALL exhibiting the BCR::ABL1-like subtype or harboring TP53 alterations is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT01564784.
Subject(s)
Inotuzumab Ozogamicin , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Inotuzumab Ozogamicin/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Adult , Female , Male , Middle Aged , Treatment Outcome , Aged , Recurrence , Antineoplastic Agents, Immunological/therapeutic use , Young Adult , Drug Resistance, Neoplasm , AdolescentABSTRACT
Venetoclax, a highly selective, oral B-cell lymphoma 2 inhibitor, provides a robust targeted-therapy option for the treatment of chronic lymphocytic leukemia (CLL), including patients with high-risk del(17p)/mutated-TP53 and immunoglobulin heavy variable region unmutated CLL and those refractory to chemoimmunotherapy across all age groups. Due to the potent pro-apoptotic effect of venetoclax, treatment initiation carries a risk of tumor lysis syndrome (TLS). Prompt and appropriate management is needed to limit clinical TLS, which may entail serious adverse events and death. Venetoclax ramp-up involves gradual, stepwise increases in daily venetoclax dosing from 20 mg to 400 mg (target dose) over 5 weeks; adherence to on-label scheduling provides a tumor debulking phase, reducing the risk of TLS. The key components of safe venetoclax therapy involve assessment (radiographic evaluation and baseline blood chemistry), preparation (adequate hydration), and initiation (blood chemistry monitoring). In addition to summarizing the evidence for venetoclax's efficacy and safety, this review uses hypothetical patient scenarios based on risk level for TLS (high, medium, low) to share the authors' clinical experience with venetoclax initiation and present global approaches utilized in various treatment settings. These hypothetical scenarios highlight the importance of a multidisciplinary approach and shared decision-making, outlining best practices for venetoclax initiation and overall optimal treatment strategies in patients with CLL.
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INTRODUCTION: U.S. veterans in the Veterans Affairs (VA) Healthcare System are managed in a national single-payer system with access to FDA-approved therapies. Prescribing patterns and outcomes of patients with CLL manage in the VA system are described. PATIENTS AND METHODS: This is a retrospective analysis of adult patients diagnosed with CLL managed in the VA from January 1999 through December 2020. First line treatment patterns are trended over 20 years. Factors associated with survival were analyzed in both untreated and treated patients. RESULTS: In the final analysis, 16,331 patients with CLL were included. The median overall survival (OS) for the whole cohort was 8.7 years (95% confidence interval [CI], 8.6-8.9). The median OS from diagnosis was 8.9 years (95% CI, 8.6-9.2 in untreated patients with CLL. In treated patients, the median time to first line treatment was 1.9 years (range, 0-21 years), and the median OS from initiation of treatment was 5.0 years (95% CI, 4.8-5.2). First line treatments varied over time, consistent with FDA approval of targeted therapies. Exposure to targeted therapies as either first line or in subsequent lines of therapy was associated longer survival: median OS of 8.5 years (95% CI, 8.0-9.1) compared to 3.5 years (95% CI, 3.5-3.9) in patients who never received targeted therapy (P < .0001). CONCLUSION: Patients treated in the VA have received therapies in line with current evidence-based treatment practices over the past 20 years. Treatment with targeted therapies is associated with longer median OS both in the first line and relapsed/refractory setting.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Veterans , Adult , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Retrospective StudiesABSTRACT
OBJECTIVE: There are significant disparities in outcomes among Hispanic patients with acute lymphoblastic leukemia (ALL). Recent studies have demonstrated favorable outcomes of pegaspargase-containing ALL regimens (PEG-CAR) in young adults however, outcomes in Hispanic ethnicity continue to be underreported. METHODS: We evaluated outcomes of newly diagnosed, adult B-cell ALL Hispanic and non-Hispanic patients consecutively treated with a PEG-CAR or HyperCVAD between January 2011 and November 2022. The primary endpoint was event-free survival (EFS) while secondary endpoints included cumulative incidence of relapse and overall survival (OS). RESULTS: Among 105 included patients, 48 (45.7%) were treated with a PEG-CAR and 57 (54.3%) with HyperCVAD. Median age was 38 years (range, 18-75 years), 61% were Hispanic, and 35.2% had poor-genetic risk. Hispanic patients demonstrated significantly worse 5-year EFS with a PEG-CAR compared to that seen with HyperCVAD (HR, 2.58; 95% CI, 1.32-5.04; p = .006) whereas non-Hispanic patients had better outcomes with PIR (52.4% vs. 42.0%). Hispanic ethnicity (p = .015) and male sex (p = .019) were independent predictors for poor OS. CONCLUSIONS: Hispanic patients with B-cell ALL had worse EFS with a PEG-CAR as compared with HyperCVAD. Future studies will aim to confirm these findings and establish a tailored treatment approach for this high-risk population.
Subject(s)
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Young Adult , Humans , Male , Adult , Asparaginase/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Polyethylene Glycols/adverse effects , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Retrospective StudiesABSTRACT
WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck. HOW WAS THE RESEARCH DONE?: The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL. WHAT WERE THE RESULTS?: After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).
Subject(s)
Adenine/analogs & derivatives , Leukemia, Lymphocytic, Chronic, B-Cell , Lymphoma, B-Cell , Pyrimidines , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Piperidines/therapeutic use , Pyrazoles/adverse effects , Lymphoma, B-Cell/drug therapyABSTRACT
INTRODUCTION: Despite recent advances in diagnosis, prognostication, and treatment options, chronic lymphocytic leukemia (CLL) is still a largely incurable disease. New concepts on diagnosis, staging, treatment, and follow-up on CLL have been incorporated throughout recent years. The lack of regional consensus guidelines has led to varying practices in the management of patients with CLL in the region. AIM: This manuscript aims to reach a consensus among expert hematologists regarding the definitions, classifications, and related practices of CLL. The experts developed a set of statements utilizing their personal experience together with the current literature on CLL management. This consensus aims to provide guidance for healthcare professionals involved in the management of CLL and serves as a step in developing regional guidelines. METHODS: Eight experts responded to 50 statements regarding the diagnosis, staging, treatment, and prognosis of CLL with three potential answering alternatives ranging between agree, disagree, and abstain. This consensus adopted a modified Delphi consensus methodology. A consensus was reached when at least 75% of the agreement to the answer were reached. This manuscript presents the scientific insights of the participating attendees, panel discussions, and the supporting literature review. RESULTS: Of the 50 statements, a consensus was reached on almost all statements. Statements covered CLL-related topics, including diagnostic evaluation, staging, risk assessment, different patient profiles, prognostic evaluation, treatment decision, therapy sequences, response evaluation, complications, and CLL during the COVID-19 pandemic. DISCUSSION/CONCLUSION: In recent years, CLL management has progressed significantly with many diagnostic tests and several novel treatments becoming available. This consensus gathers decades of consolidated principles, novel research, and promising prospects for the management of this disease.
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OBJECTIVE: The purpose of this analysis was to assess health-related quality of life (HRQoL) in patients treated with zanubrutinib and ibrutinib in the ALPINE trial (NCT03734016). METHODS: HRQoL was measured by the EORTC QLQ-C30 and EQ-5D-5L at baseline, cycle 1, and every third cycle until the end of treatment. Key patient-reported outcome (PRO) endpoints included global health status (GHS), physical and role functioning, as well as symptoms of fatigue, pain, diarrhea, and nausea/vomiting. A mixed model repeated-measure analysis using key PRO endpoints at key clinical cycles (cycles 7 and 13) was performed. RESULTS: 652 patients were randomized to receive zanubrutinib (n = 327) or ibrutinib (n = 325). By cycle 7, GHS scores improved with zanubrutinib versus ibrutinib, and in cycle 13, GHS scores remained higher in the zanubrutinib arm. The zanubrutinib arm experienced clinically meaningful improvements in physical and role functioning, as well as pain and fatigue symptoms at both cycles. Patients in the zanubrutinib arm reported lower diarrhea scores. Nausea/vomiting scores maintained in both arms. EQ-VAS scores showed greater improvement from baseline at both cycle 7 (7.92 versus 3.44) and cycle 13 (7.75 versus 3.92) of treatment with zanubrutinib compared to ibrutinib, respectively. CONCLUSIONS: Patients with R/R CLL/SLL treated with zanubrutinib demonstrated improvement versus ibrutinib in the GHS scale at cycle 7. Other endpoints continued to improve, suggesting treatment with zanubrutinib positively affected HRQoL over time. Given the generally good HRQoL at baseline in both arms, the differences between the arms were not significant.
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Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) achieves durable remissions, with flattening of the progression-free survival (PFS) curve in patients with mutated immunoglobulin heavy chain variable gene (IGHV-M). We updated long-term follow-up results from the original 300-patient FCR study initiated at MD Anderson in 1999. The current median follow-up is 19.0 years. With this extended follow-up, the median PFS for patients with IGHV-M was 14.6 years vs 4.2 years for patients with unmutated IGHV (IGHV-UM). Disease progression beyond 10 years was uncommon. In total, 16 of 94 (17%) patients in remission at 10 years subsequently progressed with the additional follow-up compared with the patients in our prior report in 2015. Only 4 of 45 patients (9%) with IGHV-M progressed beyond 10 years. Excluding Richter transformation, 96 of 300 patients (32%) developed 106 other malignancies, with 19 of 300 (6.3%) developing therapy-related myeloid neoplasms (tMNs), which were fatal in 16 of 19 (84%). No pretreatment patient characteristics predicted the risk of tMNs. In summary, FCR remains an option for patients with IGHV-M chronic lymphocytic leukemia (CLL), with a significant fraction achieving functional cure of CLL. A risk-benefit assessment is warranted when counseling patients, balancing potential functional cure with the risk of late relapses and serious secondary malignancies.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Rituximab , Follow-Up Studies , Treatment Outcome , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide , VidarabineSubject(s)
Leukemia , Lymphoma , Humans , Leukemia/diagnosis , Leukemia/therapy , Lymphoma/diagnosis , Lymphoma/drug therapy , Medical OncologyABSTRACT
ELEVATE-RR demonstrated noninferior progression-free survival and lower incidence of key adverse events (AEs) with acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia. We further characterize AEs of acalabrutinib and ibrutinib via post hoc analysis. Overall and exposure-adjusted incidence rate was assessed for common Bruton tyrosine kinase inhibitor-associated AEs and for selected events of clinical interest (ECIs). AE burden scores based on previously published methodology were calculated for AEs overall and selected ECIs. Safety analyses included 529 patients (acalabrutinib, n = 266; ibrutinib, n = 263). Among common AEs, incidences of any-grade diarrhea, arthralgia, urinary tract infection, back pain, muscle spasms, and dyspepsia were higher with ibrutinib, with 1.5- to 4.1-fold higher exposure-adjusted incidence rates. Incidences of headache and cough were higher with acalabrutinib, with 1.6- and 1.2-fold higher exposure-adjusted incidence rate, respectively. Among ECIs, incidences of any-grade atrial fibrillation/flutter, hypertension, and bleeding were higher with ibrutinib, as were exposure-adjusted incidence rates (2.0-, 2.8-, and 1.6-fold, respectively); incidences of cardiac events overall (the Medical Dictionary for Regulatory Activities system organ class) and infections were similar between arms. Rate of discontinuation because of AEs was lower for acalabrutinib (hazard ratio, 0.62; 95% confidence interval, 0.41-0.93). AE burden score was higher for ibrutinib vs acalabrutinib overall and for the ECIs atrial fibrillation/flutter, hypertension, and bleeding. A limitation of this analysis is its open-label study design, which may influence the reporting of more subjective AEs. Overall, event-based analyses and AE burden scores demonstrated higher AE burden overall and specifically for atrial fibrillation, hypertension, and hemorrhage with ibrutinib vs acalabrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02477696.
Subject(s)
Atrial Fibrillation , Hypertension , Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Atrial Fibrillation/drug therapy , Hemorrhage/chemically induced , Hypertension/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Protein Kinase Inhibitors/adverse effectsABSTRACT
PURPOSE: Acquired mutations in Bruton's tyrosine kinase (BTK) or phospholipase C-γ2 (PLCG2) genes are associated with clinical progressive disease (PD) in patients with chronic lymphocytic leukemia (CLL) treated with BTK inhibitors. Data on mutation rates in patients without PD on ibrutinib treatment are limited. EXPERIMENTAL DESIGN: We evaluated frequency and time to detection of BTK and PLCG2 mutations in peripheral blood samples from 388 patients with previously untreated (n = 238) or relapsed/refractory (n = 150) CLL across five clinical trials. RESULTS: With median follow-up of 35 months (range, 0-72) without PD at last sampling, mutations in BTK (3%), PLCG2 (2%), or both genes (1%) were rare in previously untreated patients. With median follow-up of 35 months (range, 1-70) without PD at last sample, mutations in BTK (30%), PLCG2 (7%), or both genes (5%) were more common in patients with relapsed/refractory CLL. Median time to first detection of BTK C481S mutation was not reached in previously untreated patients and was >5 years in patients with relapsed/refractory CLL. Among patients evaluable at PD, previously untreated patients (n = 12) had lower rates than those with relapsed/refractory disease (n = 45) of BTK (25% vs. 49%) and PLCG2 mutations (8% vs. 13%). Time from first detection of BTK C481S mutation to PD was 11.3 months in 1 previously untreated patient and median 8.5 months (range, 0-35.7) among 23 patients with relapsed/refractory CLL. CONCLUSIONS: This systematic investigation describes development of mutations over time in patients without PD and informs the potential clinical opportunity to optimize ongoing benefits for such patients.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Mutation , Agammaglobulinaemia Tyrosine Kinase , Receptors, Antigen, B-Cell/metabolismABSTRACT
BACKGROUND: Historically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting. METHODS: Mini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 courses, and blinatumomab for 4 additional courses. RESULTS: Among 110 patients (median age, 37 years) treated, 91 (83%) responded (complete response, 69 patients, 63%). Measurable residual disease negativity was documented in 75 patients (82% of responders). Fifty-three patients (48%) received allogeneic stem cell transplantation (SCT). Hepatic sinusoidal obstruction syndrome occurred in 9/67 patients (13%) on the original inotuzumab schedule and in 1/43 (2%) on the modified schedule. With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini-Hyper-CVD plus inotuzumab and 52% with additional blinatumomab (P = 0.16). By landmark analysis at 4 months, the 3 year OS was 54%, similar between patients who did or did not receive allogeneic SCT. CONCLUSION: Low-intensity mini-Hyper-CVD plus inotuzumab with or without blinatumomab showed efficacy in patients with relapsed-refractory ALL, with better survival after the addition of blinatumomab. Trial registration The trial was registered on clinicaltrials.gov with the identifier NCT01371630.
Subject(s)
Antibodies, Bispecific , Cardiovascular Diseases , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Adult , Humans , Antibodies, Bispecific/adverse effects , Cardiovascular Diseases/chemically induced , Inotuzumab Ozogamicin/therapeutic use , Methotrexate/therapeutic use , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Salvage Therapy/methodsABSTRACT
BACKGROUND: Since the emergence of neurosurgery as a distinct specialty â¼100 years ago in Canada, it took >40 years for Canadian women to enter the field in the province of Quebec, and longer in the other provinces. METHODS: We provide a historical overview of Canadian women in neurosurgery, from the early pioneers to the modern-day leaders and innovators in the field. We also define the current participation of women in Canadian neurosurgery. Chain-referral sampling, historical books, interviews, personal communications, and online resources were used as data sources. RESULTS: Our historical review highlights the exceptional journey and unique experiences of female neurosurgeons, describes their achievements, and identifies career obstacles and enabling factors. We also incorporate comments from Canadian female neurosurgeons, both retired and in active practice, addressing gender inequities in the field, and provide advice and encouragement to the new generations to come. Despite the achievements of these female trailblazers, women represent a small proportion of the Canadian neurosurgery trainees and the active workforce, in stark contrast to the increasing number of women in medical school. CONCLUSIONS: To the best of our knowledge, this study represents the first historical overview of female women neurosurgeons in Canada. Providing a historical context will help us to better understand the important role of women in modern neurosurgery, identify persistent gender issues in the field, and provide a vision for aspiring female neurosurgeons.
Subject(s)
Neurosurgery , Humans , Female , Canada , Neurosurgeons , Workforce , SexismABSTRACT
Treatment of acute lymphoblastic leukemia (ALL) requires both systemically and locally directed therapies to prevent central nervous system (CNS) recurrence. In response to restrictions brought on by the COVID-19 pandemic, our institution adopted triple intrathecal (IT) chemotherapy for CNS prophylaxis during HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine). We retrospectively reviewed records of newly diagnosed adult all patients who were consecutively treated with HyperCVAD between January 2011 and July 2022. Outcomes of patients who received triple IT chemotherapy and standard of care (SOC) CNS prophylaxis were compared. The primary endpoint was CNS relapse-free survival (RFS) while secondary endpoints included cumulative incidence of relapse, overall survival, number of outpatient, and total ITs per patient, and CNS treatment-related toxicities. A total of 37 patients including 21 in the triple IT and 16 in the SOC cohorts were evaluated. There were no differences between the triple IT and SOC cohorts with respect to CNS-RFS (89.6% vs. 80.4%; HR, 1.55; 95% CI, 0.45-5.39; p = .49), cumulative incidence of relapse (8.9% vs. 19.6%; HR, 1.14; 95% CI, 0.3-5.3; p = .87), and overall survival (89.6% vs. 85.7%; HR, 0.91; 95% CI, 0.20-4.21; p = .90) at 2-years. Significantly fewer IT doses were administered in the triple IT cohort (p = .011) and the number of additional outpatient appointments to administer IT chemotherapy were markedly reduced as 98.6% of IT doses were administered during scheduled admissions compared to 76.8% (p < .001). The adoption of triple IT chemotherapy did not increase CNS treatment-related toxicities but rather, the inverse was observed. Triple IT chemotherapy during HyperCVAD represents a feasible alternative to SOC CNS prophylaxis, especially during times of resource restriction and when minimization of patient exposures is desired.
Subject(s)
COVID-19 , Central Nervous System Neoplasms , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Adult , Retrospective Studies , Pandemics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , COVID-19/epidemiology , COVID-19/prevention & control , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Cyclophosphamide/therapeutic use , Methotrexate/therapeutic use , Recurrence , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/prevention & control , Vincristine/adverse effectsABSTRACT
Cellular therapies can be viewed as both the newest and oldest techniques for treating chronic lymphocytic leukemia (CLL) and Richter's transformation (RT). On one hand, allogeneic hematopoietic stem cell transplantation (alloHSCT) has been available for decades, though its use is diminishing with the increasing availability of effective novel targeted agents, especially in CLL. Among newer techniques, chimeric antigen receptor T-cells (CAR-T) have demonstrated astounding efficacy in several hematologic malignancies, leading to FDA approval and use in clinical practice. However, though CLL is the earliest disease type for which CAR-T were studied, development has been slower and has yet to lead to regulatory approval. Owing partially to its rarity but also due to the aggressive behavior of RT, CAR-T in RT have only been minimally explored. Here, we will focus on the applications of cellular therapies in CLL and RT, specifically reviewing more recent data related to alloHSCT in the novel-agent era and CAR-T cell development in CLL/RT, focusing on safety and efficacy successes and limitations. We will review strategies to improve upon CAR-T efficacy and discuss ongoing trials utilizing CAR-T in CLL/RT, as well as emerging technologies, such as allogeneic CAR-T and natural killer CAR (CAR NK) cells.