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PURPOSE: AML presenting with hyperleukocytosis is associated with poor outcomes. We aim to understand the factors associated with early mortality and overall survival (OS) to help guide management and improve early mortality. METHODS: We retrospectively reviewed data from 129 consecutive patients with newly diagnosed AML and a WBC count ≥100 × 109/L between January 2010 and April 2020. Logistic regression models estimated odds ratios for 4-week mortality. Cox proportional hazard models estimated hazard ratios for OS. RESULTS: The median age was 65 years (range, 23-86); the median WBC was 146 × 109/L (range, 100-687). Seventy-five (58%) patients had clinical leukostasis (CL). FLT3, NPM1, and RAS pathway mutations were detected in 63%, 45%, and 27% of patients, respectively. Cytoreduction consisted of hydroxyurea in 124 (96%) patients, cytarabine in 69 (54%), and leukapheresis in 31 (24%). The cumulative 4-week and 8-week mortality rates were 9% and 13%, respectively, all in patients age 65 years and older. By multivariate analysis, older age, CL, and thrombocytopenia <40 × 109/L were independently associated with a higher 4-week mortality rate. After a median follow-up of 49.4 months, the median OS was 14.3 months (95% CI, 7 to 21.6), with 4-year OS of 29%. Age 65 years and older, CL, tumor lysis syndrome, elevated LDH ≥2,000 U/L, elevated lactate ≥2.2 mmol/L, and poor-risk cytogenetics were independent factors associated with worse OS. CONCLUSION: Hyperleukocytosis is a life-threatening hematologic emergency. Early recognition and intervention including cytoreduction, blood product support, antibiotics, and renal replacement therapy may help mitigate the risk of morbidity and early mortality.
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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In this analysis, we update our experience with the chemotherapy-free regimen of blinatumomab and ponatinib in 60 patients with newly diagnosed Philadelphia chromosome (Ph)-positive ALL. At a median follow-up of 24 months, the complete molecular response rate by reverse transcriptase-polymerase chain reaction was 83% (67% at the end of course one), and the rate of measurable residual disease negativity by next-generation clono-sequencing was 98% (45% at the end of course one). Only two patients underwent hematopoietic stem cell transplantation (HSCT). Seven patients relapsed: two with systemic disease, four with isolated CNS relapse, and one with extramedullary Ph-negative, CRLF2-positive pre-B ALL. The estimated 3-year overall survival rate was 91% and event-free survival rate was 77%. Three patients discontinued blinatumomab because of adverse events (related, n = 1; unrelated, n = 2) and nine discontinued ponatinib because of cerebrovascular ischemia, coronary artery stenosis, persistent rash, elevated liver function tests with drug-induced fatty liver, atrial thrombus, severe arterial occlusive disease of lower extremities, pleuro-pericardial effusion, and debilitation. In conclusion, the simultaneous combination of ponatinib and blinatumomab is a highly effective and relatively safe nonchemotherapy regimen. This regimen also reduces the need for intensive chemotherapy and HSCT in first remission in the majority of patients.
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STUDY AIMS: To evaluate the outcomes of patients with 3q26.2/MECOM-rearranged chronic myeloid leukemia (CML). METHODS: We reviewed consecutive adult patients with 3q26.2/MECOM-rearranged CML between January 1, 1998 and February 16, 2023. Rearrangements of 3q26.2/MECOM were confirmed by conventional cytogenetics, and fluorescence in situ hybridization starting in 2015. RESULTS: We identified 55 patients with MECOM-rearranged CML, including 23 in chronic phase (CP) or accelerated phase (AP) and 32 in blast phase (BP). Nine patients (16%) achieved a major cytogenetic response (MCyR) or deeper. At a median follow-up of 89 months, median survival was 14 months. The 5-year survival rate was 19% overall, 23% in CML-CP/AP, and 15% in CML-BP. In the 6-month landmark analysis, the 5-year survival rate was 41% for allogeneic stem cell transplantation (allo-SCT) recipients versus 17% for non-recipients (P = 0.050). Multivariate analysis showed that the percentage of marrow blasts and achievement of MCyR or deeper could predict survival. CONCLUSION: Outcomes of 3q26.2/MECOM-rearranged CML are poor despite the availability of multiple BCR::ABL1 tyrosine kinase inhibitors (TKIs). Third-generation TKIs in combination with novel agents and possible allo-SCT could be considered given the poor outcomes and resistance to second-generation TKIs.
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Chromosomes humains de la paire 3 , Réarrangement des gènes , Leucémie myéloïde chronique BCR-ABL positive , Humains , Adulte , Adulte d'âge moyen , Mâle , Femelle , Leucémie myéloïde chronique BCR-ABL positive/génétique , Leucémie myéloïde chronique BCR-ABL positive/thérapie , Leucémie myéloïde chronique BCR-ABL positive/mortalité , Leucémie myéloïde chronique BCR-ABL positive/diagnostic , Chromosomes humains de la paire 3/génétique , Sujet âgé , Taux de survie , Jeune adulte , Résultat thérapeutique , Études rétrospectives , Adolescent , Études de suiviRÉSUMÉ
Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with high potency against Philadelphia chromosome (Ph)-positive leukemias, including T315I-mutated disease, which is resistant to first- and second-generation TKIs. Ponatinib was approved for T315I-mutated chronic myeloid leukemia (CML), CML resistant/intolerant to ≥2 prior TKIs, advanced phase CML and Ph-positive acute lymphoblastic leukemia (ALL) where no other TKIs are indicated, and T315I-mutated CML and Ph-positive ALL. The response-based dosing of ponatinib in chronic phase CML (CP-CML) improved treatment tolerance and reduced the risk of toxicities, including cardiovascular risks. Ponatinib-based therapy also resulted in significantly better outcomes in frontline Ph-positive ALL compared with prior TKIs and is becoming a new standard of care in this setting. As the clinical development of third-generation TKIs and their rational combinations progresses, we envision further transformative changes in the treatment of CML and Ph-positive ALL.
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Protéines de fusion bcr-abl , Imidazoles , Leucémie myéloïde chronique BCR-ABL positive , Inhibiteurs de protéines kinases , Pyridazines , Humains , Pyridazines/usage thérapeutique , Pyridazines/effets indésirables , Imidazoles/usage thérapeutique , Leucémie myéloïde chronique BCR-ABL positive/traitement médicamenteux , Inhibiteurs de protéines kinases/usage thérapeutique , Protéines de fusion bcr-abl/antagonistes et inhibiteurs , Protéines de fusion bcr-abl/génétique , Leucémie-lymphome lymphoblastique à précurseurs B et T/traitement médicamenteux , Antinéoplasiques/usage thérapeutique , Résistance aux médicaments antinéoplasiquesRÉSUMÉ
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.
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BACKGROUND: Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome-positive leukemias. Herein, we report the long-term follow-up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. METHODS: Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6-month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. RESULTS: Fifty-one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21-75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2-25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second-line TKI (n = 34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6-month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24-month event-free survival rate was 97%. After a median follow-up of 128 months, the 10-year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). CONCLUSION: Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio-/vaso-occlusive and other severe toxicities.
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Imidazoles , Chromosome Philadelphie , Leucémie-lymphome lymphoblastique à précurseurs B et T , Pyridazines , Récidive , Humains , Pyridazines/usage thérapeutique , Pyridazines/effets indésirables , Pyridazines/administration et posologie , Leucémie-lymphome lymphoblastique à précurseurs B et T/traitement médicamenteux , Imidazoles/usage thérapeutique , Imidazoles/effets indésirables , Imidazoles/administration et posologie , Mâle , Femelle , Adulte d'âge moyen , Sujet âgé , Adulte , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/effets indésirables , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/effets indésirablesRÉSUMÉ
BACKGROUND: The dual inhibition of the BCR::ABL1 tyrosine kinase and BCL-2 could potentially deepen the response rates of chronic myeloid leukemia in chronic phase (CML-CP). This study evaluated the safety and efficacy of the combination of dasatinib and venetoclax. METHODS: In this phase 2 trial, patients with CML-CP or accelerated phase (clonal evolution) received dasatinib 50 mg/day for three courses; venetoclax was added in course 4 for 3 years. The initial venetoclax dose was 200 mg/day continuously but reduced later to 200 mg/day for 14 days, and to 100 mg/day for 7 days per course once a molecular response (MR)4.5 was achieved. After 3 years of combination, patients were maintained on single-agent dasatinib. The primary end point was the rate of major molecular response (MMR) by 12 months of combination. RESULTS: Sixty-five patients were treated. Their median age was 46 years (range, 23-73). By 12 months of combination, the MMR, MR4, and MR4.5 rates were 86%, 53%, and 45%, respectively. After a median follow-up of 42 months, the 4-year event-free and overall survival rates were 96% and 100%, respectively. Outcomes with the combination were comparable to historical outcomes with single-agent dasatinib (cumulative 12-months MMR rate of 79% with both strategies). The incidence of grade 3-4 neutropenia was 22% with the combination and 11% with single-agent dasatinib (p < .001). CONCLUSIONS: Treatment with dasatinib and venetoclax was safe and effective in CML-CP. The cumulative response rates with the combination were similar to those with single-agent dasatinib. Further follow-up is needed to evaluate the rates of durable deep molecular response and treatment-free remission.
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Protocoles de polychimiothérapie antinéoplasique , Composés hétérocycliques bicycliques , Dasatinib , Sulfonamides , Humains , Dasatinib/administration et posologie , Dasatinib/usage thérapeutique , Dasatinib/effets indésirables , Adulte d'âge moyen , Composés hétérocycliques bicycliques/administration et posologie , Composés hétérocycliques bicycliques/usage thérapeutique , Composés hétérocycliques bicycliques/effets indésirables , Adulte , Femelle , Sujet âgé , Sulfonamides/administration et posologie , Sulfonamides/usage thérapeutique , Sulfonamides/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Mâle , Jeune adulte , Leucémie myéloïde en phase chronique/traitement médicamenteux , Leucémie myéloïde en phase chronique/génétiqueRÉSUMÉ
Patients with chronic myeloid leukemia in chronic phase (CML-CP) can have a normal life expectancy when treated with the BCR::ABL1 tyrosine kinase inhibitors. In recent years, treatment discontinuation and treatment-free remission (TFR) emerged as the new goal of therapy in patients with CML-CP. Deep and sustained molecular remissions for more than 3 to 5 years are associated with higher chances of a successful TFR. However, although uncommon, some patients may still experience molecular or hematological relapse after treatment discontinuation, even after a prolonged duration of remission. In this case series, we report the outcome of four patients with CML-CP who were treated with tyrosine kinase inhibitors and achieved a deep molecular response for ≥8 years, but eventually experienced disease relapse after treatment discontinuation. We discuss the importance of regular monitoring after treatment discontinuation as well as future strategies to increase the chances of TFR in patients with CML-CP.
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Aberrations des chromosomes , Leucémie myéloïde chronique BCR-ABL positive , Chromosome Philadelphie , Induction de rémission , Humains , Leucémie myéloïde chronique BCR-ABL positive/génétique , Leucémie myéloïde chronique BCR-ABL positive/traitement médicamenteux , Mâle , Femelle , Adulte d'âge moyen , Adulte , Sujet âgéSujet(s)
Protéines de fusion bcr-abl , Leucémie myéloïde chronique BCR-ABL positive , Humains , Protéines de fusion bcr-abl/antagonistes et inhibiteurs , Protéines de fusion bcr-abl/génétique , Leucémie myéloïde chronique BCR-ABL positive/traitement médicamenteux , Leucémie myéloïde chronique BCR-ABL positive/génétique , Protéines proto-oncogènes c-abl/génétique , Protéines proto-oncogènes c-abl/antagonistes et inhibiteurs , /usage thérapeutiqueSujet(s)
Dasatinib , Leucémie myéloïde chronique BCR-ABL positive , Inhibiteurs de la pompe à protons , Humains , Dasatinib/usage thérapeutique , Dasatinib/effets indésirables , Leucémie myéloïde chronique BCR-ABL positive/traitement médicamenteux , Inhibiteurs de la pompe à protons/usage thérapeutique , Inhibiteurs de la pompe à protons/effets indésirables , Mâle , Femelle , Adulte d'âge moyen , Sujet âgé , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/effets indésirables , Adulte , Résultat thérapeutique , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/effets indésirablesRÉSUMÉ
Over the past several years, advances in research, treatment, and market dynamics have impacted treatment strategies in chronic myeloid leukemia in chronic phase (CML-CP). They include the broader availability of cost-effective generic imatinib, and soon other generic second-generation tyrosine kinase inhibitors (TKIs). Access to affordable generics means that all patients with CML-CP should have access to safe and highly effective lifelong therapies. When overall survival is the treatment endpoint, imatinib provides a good treatment value. Second-generation TKIs may be the best frontline strategy when treatment-free remission is the goal. Recent studies have shown maintained efficacy and reduced toxicity when TKIs are used at reduced dosing. Reduced-dose schedules of second-generation TKIs (which are less toxic and induce faster deep molecular responses) may render generic second-generation TKIs a more attractive treatment option. Adjusting the dose of TKI in the presence of mild-to-moderate, or even severe but reversible, adverse events may be preferable to switching to a different TKI. The selection of second-line and beyond therapies depends on the evolving patterns observed with frontline treatment. Dose-adjusted ponatinib schedules have demonstrated improved efficacy and safety in patients resistant to second-generation TKIs or those with T315I-mutated disease. For asciminib, longer-term follow-up is needed to better evaluate its safety and efficacy compared with ponatinib. Allogeneic stem cell transplantation represents a valid alternative to newer-generation TKIs, with a better treatment value when TKIs are priced at >$40,000/year.
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Antinéoplasiques , Leucémie myéloïde chronique BCR-ABL positive , Leucémie myéloïde en phase chronique , Humains , Mésilate d'imatinib/usage thérapeutique , Antinéoplasiques/effets indésirables , Inhibiteurs de protéines kinases , Leucémie myéloïde en phase chronique/traitement médicamenteux , Leucémie myéloïde chronique BCR-ABL positive/traitement médicamenteux , Leucémie myéloïde chronique BCR-ABL positive/génétique , Médicaments génériques/usage thérapeutique , Protéines de fusion bcr-abl/génétiqueRÉSUMÉ
The outcome of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) has improved significantly following the introduction of the BCR::ABL1 tyrosine kinase inhibitors (TKIs). The addition of newer-generation and more potent TKIs resulted in higher rates of molecular responses and better survival. Achieving a complete molecular remission (CMR; disappearance of the BCR::ABL1 transcripts) within the first 3 months of therapy is an important endpoint in newly diagnosed Ph-positive ALL that identifies patients who have an excellent long-term survival and who may not need to receive an allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Chemotherapy-free combinations with blinatumomab plus TKIs showed encouraging results with estimated 2 to 4 year overall survival (OS) rates of 80% to 90%. Treatment with blinatumomab and ponatinib resulted in a CMR rate of 84%, a 2-year event-free survival (EFS) of 78%, and a 2-year OS rate of 90%; only 1 patient underwent HSCT. The detection of measurable residual disease (MRD) is the most important factor predicting for disease relapse. Studies have shown that the next-generation sequencing (NGS) assay is more sensitive than RT-PCR for the detection of MRD in Ph-positive ALL. Approximately 15% to 30% of patients who achieve NGS MRD negativity at a sensitivity of 1 × 10-6 may still have detectable BCR::ABL1 transcripts by RT-PCR. Achieving NGS MRD negativity can also identify patients who may have durable remissions with a low risk of relapse. Herein, we discuss the current approach to the management of adults with Ph-positive ALL, the role of HSCT, MRD monitoring, and future therapies.
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Leucémie-lymphome lymphoblastique à précurseurs B et T , Humains , Leucémie-lymphome lymphoblastique à précurseurs B et T/thérapie , Leucémie-lymphome lymphoblastique à précurseurs B et T/traitement médicamenteux , Leucémie-lymphome lymphoblastique à précurseurs B et T/mortalité , Leucémie-lymphome lymphoblastique à précurseurs B et T/génétique , Chromosome Philadelphie , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/pharmacologie , Transplantation de cellules souches hématopoïétiques/méthodes , Protéines de fusion bcr-abl/génétique , Maladie résiduelleRÉSUMÉ
The integration of immune and targeted therapies into the treatment of acute lymphoblastic leukemia (ALL) has significantly improved outcomes, reduced the intensity and duration of chemotherapy, and the reliance on allogeneic stem cell transplantation (SCT). In younger patients with Philadelphia chromosome (Ph)-negative ALL, treatment with Hyper-CVAD and blinatumomab +/- inotuzumab has improved the 3-year overall survival (OS) to above 85%. In older patients, using less intensive chemotherapy (mini-Hyper-CVD) in combination with inotuzumab and blinatumomab has improved the 5-year OS rate to 50%. In Ph+ ALL, the chemotherapy-free combinations of blinatumomab and ponatinib (or dasatinib) have become a new standard of care resulting in 3-year OS of 85% to 90%. Because the methotrexate-cytarabine courses were omitted in the nonchemotherapy regimens, central nervous system (CNS) relapses were noted, particularly in patients with a WBC count > 70 × 109/L, requiring to consider increasing the number of prophylactic intrathecals (from 12 to 15) and perhaps developing a CNS risk-directed high-dose systemic chemotherapy. In relapsed/refractory ALL, a dose-dense regimen integrating blinatumomab and inotuzumab with low-intensity chemotherapy followed by consolidation with chimeric antigen receptor T-cell therapy is being investigated. The detection of measurable residual disease (MRD) following ALL therapy is predictive of disease relapse. Using next-generation sequencing allows the detection of MRD at 1 × 10-6 which was shown to be superior to multiparameter flow cytometry and polymerase chain reaction in predicting relapse, and could be used to decide on the duration of therapy or need to change therapy. Herein, we review the recent updates and areas of unmet need in ALL.
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Leucémie-lymphome lymphoblastique à précurseurs B et T , Humains , Leucémie-lymphome lymphoblastique à précurseurs B et T/thérapie , Leucémie-lymphome lymphoblastique à précurseurs B et T/traitement médicamenteux , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutiqueRÉSUMÉ
BACKGROUND: The combination of low-intensity chemotherapy and inotuzumab ozogamicin (INO), with sequential blinatumomab, is highly effective in older adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and in relapsed or refractory B-cell ALL. Earlier, "dose-dense" administration of blinatumomab could lead to earlier and deeper measurable residual disease (MRD) responses and better outcomes. PATIENTS AND METHODS: We performed a retrospective analysis of the safety and efficacy of a dose-dense regimen of mini-hyper-CVD (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with mini-methotrexate and cytarabine), INO, and blinatumomab in patients with B-cell ALL. RESULTS: Twenty-one patients were treated (frontline, n = 9; MRD consolidation, n = 4; relapsed/refractory, n = 8). In the frontline cohort, all patients achieved CR/CRi and MRD negativity by flow cytometry at the end of cycle 1. Across the frontline and MRD consolidation cohorts, 10/11 patients (91%) achieved next-generation sequencing MRD negativity at a sensitivity of 10-6, including 6/10 evaluable patients (60%) who achieved next-generation sequencing MRD negativity after cycle 1. The CR/CRi rate in the relapsed/refractory cohort was 63%, and all responders achieved MRD negativity by flow cytometry at the end of cycle 1. The 1-year overall survival rate for the combined cohort of the frontline and MRD-positive patients was 83%. No new safety signals were observed with the dose-dense mini-hyper-CVD, INO, and blinatumomab regimen. CONCLUSION: Dose-dense delivery of mini-hyper-CVD, INO, and blinatumomab was safe and resulted in rapid and deep MRD negativity in patients with B-cell ALL. This regimen is now being prospectively evaluated in both the frontline and relapsed/refractory settings.
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Anticorps bispécifiques , Maladies cardiovasculaires , Leucémie-lymphome lymphoblastique à précurseurs B , Leucémie-lymphome lymphoblastique à précurseurs B et T , Humains , Sujet âgé , Inotuzumab ozogamicine/pharmacologie , Inotuzumab ozogamicine/usage thérapeutique , Études rétrospectives , Chromosome Philadelphie , Leucémie-lymphome lymphoblastique à précurseurs B et T/traitement médicamenteux , Anticorps bispécifiques/effets indésirables , Leucémie-lymphome lymphoblastique à précurseurs B/diagnostic , Leucémie-lymphome lymphoblastique à précurseurs B/traitement médicamenteux , Maladies cardiovasculaires/induit chimiquementRÉSUMÉ
ABSTRACT: Preclinical studies suggest that Bcl-2 inhibition with venetoclax has antileukemic activity in acute lymphoblastic leukemia (ALL) and may synergize with conventional chemotherapy. We designed a phase 1/2 clinical trial to evaluate the safety and efficacy of low-intensity chemotherapy in combination with venetoclax in adults with relapsed or refractory ALL. Patients received the mini-hyper-CVD regimen (dose-attenuated hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate and cytarabine) in combination with venetoclax (200 mg or 400 mg daily) on days 1 to 14 in cycle 1 and on days 1 to 7 in consolidation cycles. Twenty-two patients were treated. The median number of prior therapies was 2 (range, 1-6). Thirteen patients (59%) had undergone prior allogeneic stem cell transplant (allo-SCT), and 7 of 18 patients (39%) with B-cell ALL had previously received both inotuzumab ozogamicin and blinatumomab. The recommended phase 2 dose of venetoclax in the combination regimen was 400 mg daily. The composite complete remission (CR) and CR with incomplete hematologic recovery (CRi) rate was 57% (CR, 43%; CRi, 14%), and 45% of responders achieved measurable residual disease negativity by multiparameter flow cytometry. Four patients proceeded to allo-SCT. The median duration of response was 6.3 months. The median overall survival was 7.1 months, and the 1-year overall survival rate was 29%. The most common grade ≥3 nonhematologic adverse events were infection in 17 patients (77%) and febrile neutropenia in 4 patients (18%). Overall, the combination of mini-hyper-CVD plus venetoclax was active in heavily pretreated relapsed/refractory ALL. Further development of venetoclax-based combinations in ALL is warranted. This trial is registered at www.clinicaltrials.gov as #NCT03808610.
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Maladies cardiovasculaires , Leucémie-lymphome lymphoblastique à précurseurs B et T , Sulfonamides , Adulte , Humains , Inotuzumab ozogamicine/usage thérapeutique , Leucémie-lymphome lymphoblastique à précurseurs B et T/traitement médicamenteux , Composés hétérocycliques bicycliques/effets indésirables , Maladies cardiovasculaires/induit chimiquementRÉSUMÉ
ABSTRACT: The detection of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). Using inotuzumab ozogamicin in the setting of MRD may improve outcomes. Patients with ALL in first complete remission (CR1) or beyond (CR2+) with MRD ≥ 1 × 10-4 were enrolled in this phase 2 trial. Inotuzumab was administered at 0.6 mg/m2 on day 1 and 0.3 mg/m2 on day 8 of cycle 1, then at 0.3 mg/m2 on days 1 and 8 of cycles 2-6. Twenty-six consecutive patients with a median age of 46 years (range, 19-70 years) were treated. Nineteen (73%) were in CR1 and seven (27%) in CR2+; 16 (62%) had Philadelphia chromosome-positive ALL. Fifteen (58%) had baseline MRD ≥ 1 × 10-3. A median of 3 cycles (range, 1-6) were administered. Eighteen (69%) patients responded and achieved MRD negativity. After a median follow-up of 24 months (range, 9-43), the 2-year relapse-free survival rate was 54% and the 2-year overall survival rate was 60% in the entire cohort. Most adverse events were low grade; sinusoidal obstruction syndrome was noted in 2 patients (8%). In summary, inotuzumab ozogamicin resulted in favorable survival, MRD negativity rates, and safety profiles for patients with ALL and MRD-positive status. This study was registered at www.ClinicalTrials.gov as #NCT03441061.