ABSTRACT
PURPOSE: Artificial intelligence can reduce the time used by physicians on radiological assessments. For 18F-fluorodeoxyglucose-avid lymphomas, obtaining complete metabolic response (CMR) by end of treatment is prognostic. METHODS: Here, we present a deep learning-based algorithm for fully automated treatment response assessments according to the Lugano 2014 classification. The proposed four-stage method, trained on a multicountry clinical trial (ClinicalTrials.gov identifier: NCT01287741) and tested in three independent multicenter and multicountry test sets on different non-Hodgkin lymphoma subtypes and different lines of treatment (ClinicalTrials.gov identifiers: NCT02257567, NCT02500407, 20% holdout in ClinicalTrials.gov identifier: NCT01287741), outputs the detected lesions at baseline and follow-up to enable focused radiologist review. RESULTS: The method's response assessment achieved high agreement with the adjudicated radiologic responses (eg, agreement for overall response assessment of 93%, 87%, and 85% in ClinicalTrials.gov identifiers: NCT01287741, NCT02500407, and NCT02257567, respectively) similar to inter-radiologist agreement and was strongly prognostic of outcomes with a trend toward higher accuracy for death risk than adjudicated radiologic responses (hazard ratio for end of treatment by-model CMR of 0.123, 0.054, and 0.205 in ClinicalTrials.gov identifiers: NCT01287741, NCT02500407, and NCT02257567, compared with, respectively, 0.226, 0.292, and 0.272 for CMR by the adjudicated responses). Furthermore, a radiologist review of the algorithm's assessments was conducted. The radiologist median review time was 1.38 minutes/assessment, and no statistically significant differences were observed in the level of agreement of the radiologist with the model's response compared with the level of agreement of the radiologist with the adjudicated responses. CONCLUSION: These results suggest that the proposed method can be incorporated into radiologic response assessment workflows in cancer imaging for significant time savings and with performance similar to trained medical experts.
ABSTRACT
The Phase 2 portion of this study evaluated safety and efficacy of polatuzumab vedotin 1.8 mg/kg and venetoclax 800 mg, plus fixed-dose obinutuzumab 1000 mg or rituximab 375 mg/m2 in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), respectively. Patients with complete response (CR) or partial response (PR)/stable disease (FL) or CR/PR (DLBCL) at end of induction (EOI; six 21-day cycles) received post-induction therapy with venetoclax and obinutuzumab or rituximab, respectively. Primary endpoint was CR rate at EOI. Safety-evaluable populations included 74 patients (FL cohort; median age 64 years; progression of disease within 24 months on first-line treatment, 25.7%; FL International Prognostic Index 3-5, 54.1%; ≥2 previous therapies, 74.3%) and 57 patients (DLBCL cohort; median age 65 years; International Prognostic Index 3-5, 54.4%; ≥2 previous therapies, 77.2%). The most common non-hematologic adverse events (mostly Grades 1-2) in the FL and DLBCL cohorts were diarrhea (55.4% and 47.4%, respectively) and nausea (47.3% and 36.8%); neutropenia was the most common Grades 3-4 toxicity (39.2% and 52.6%). Efficacy-evaluable populations included patients treated at the recommended Phase 2 dose (FL, n = 49; DLBCL, n = 48). CR rates at EOI were 59.2% (FL) and 31.3% (DLBCL); median progression-free survival was 22.8 months (95% confidence interval [CI], 14.5-not evaluable) and 4.6 months (95% CI, 3.6-8.1), respectively. Polatuzumab vedotin plus venetoclax and obinutuzumab/rituximab had acceptable safety in patients with R/R FL or DLBCL, with promising response rates in R/R FL, including high-risk patients.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Bridged Bicyclo Compounds, Heterocyclic , Lymphoma, Large B-Cell, Diffuse , Rituximab , Sulfonamides , Humans , Middle Aged , Aged , Male , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Female , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Lymphoma, Large B-Cell, Diffuse/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Adult , Aged, 80 and over , Rituximab/administration & dosage , Rituximab/therapeutic use , Rituximab/adverse effects , Lymphoma, Follicular/drug therapy , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Recurrence , ImmunoconjugatesABSTRACT
BACKGROUND: Diffuse large B-cell lymphoma comprises nearly 30% of non-Hodgkin lymphoma cases and patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for stem-cell transplantation have few treatment options and poor prognoses. We aimed to determine whether the novel combination of polatuzumab vedotin in combination with rituximab and lenalidomide (Pola+R+Len) would provide a tolerable treatment option with enhanced antitumour response in patients with relapsed or refractory diffuse large B-cell lymphoma. METHODS: This completed phase 1b/2, open-label, multicentre, single-arm study (GO29834) evaluated the safety and efficacy of Pola+R+Len in patients with relapsed or refractory diffuse large B-cell lymphoma at 19 sites in three countries (USA, Spain, and UK). Patients (≥18 years old) were eligible for inclusion if they had histologically documented CD20-positive relapsed or refractory diffuse large B-cell lymphoma and Eastern Cooperative Oncology Group performance status of 2 or lower, had received at least one previous line of chemoimmunotherapy, including an anti-CD20 agent, and were ineligible for stem-cell transplantation. The dose-escalation phase (1b) used escalating doses of lenalidomide to find the recommended phase 2 dose. Patients received six 28-day cycles of induction treatment with intravenous rituximab 375 mg/m2 and intravenous polatuzumab vedotin 1·8 mg/kg (all cohorts) plus oral lenalidomide at the following doses: 10 mg (cohort A); 15 mg (cohort B); and 20 mg (cohort C). Rituximab and polatuzumab vedotin were administered on day 1 and lenalidomide on days 1-21 of each 28-day cycle. During the dose-expansion phase (2), patients received six 28-day cycles of Pola+R+Len at the recommended phase 2 dose established during dose escalation. In both phases, patients with a complete response or partial response at the end of induction were eligible for post-induction therapy with rituximab 375 mg/m2 on day 1 and lenalidomide 10 mg/day on days 1-21 of each 28-day cycle for a maximum of 6 cycles. The primary safety objective of the dose-escalation phase was identification of the maximum tolerated dose through incidence of dose-limiting toxic effects. The primary efficacy outcome of the dose-expansion phase was Independent Review Committee-assessed complete response rate at end of induction, based on PET-CT. Analyses were conducted in the safety population, which included all patients who received at least one dose of any study drug, and the efficacy population, which included all patients who received at least one dose of any study drug at the recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02600897. FINDINGS: Between July 11, 2017 and Feb 3, 2020, 57 patients were enrolled (median age 71 years [IQR 60-75]; 38 [67%] were male and 19 (33%) were female; 47 [82%] were not Hispanic or Latino; and the median previous lines of therapy was 2 [IQR 1-3]). 18 participants were included in phase 1b and 39 were included in phase 2. Phase 1b confirmed a 20 mg recommended phase 2 dose for lenalidomide. After a median follow-up of 11·8 months (IQR 4·7-25·8), the complete response rate, as assessed by the Independent Review Committee, was 31% (90% CI 20-43). The most common grade 3-4 adverse events were neutropenia (35 [61%] of 57) and thrombocytopenia (eight [14%] of 57). Serious adverse events were reported in 23 (40%) of 57 patients and one patient died due to a treatment-related adverse event (neutropenic sepsis). INTERPRETATION: Although the combination of Pola+R+Len did not meet the prespecified activity threshold, some patients derived clinical benefit and the regimen had a tolerable safety profile in patients with relapsed or refractory diffuse large B-cell lymphoma. FUNDING: Genentech/F Hoffmann-La Roche.
Subject(s)
Antibodies, Monoclonal , Immunoconjugates , Lymphoma, Large B-Cell, Diffuse , Lymphoma, Non-Hodgkin , Neutropenia , Humans , Male , Female , Aged , Adolescent , Rituximab/adverse effects , Lenalidomide/therapeutic use , Positron Emission Tomography Computed Tomography , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Neutropenia/etiologyABSTRACT
Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin lymphoma. Despite treatment advances that have improved outcomes for patients with relapsed or refractory (R/R) FL, many patients still die from progressive disease or treatment-related toxicities. In the phase Ib/II GO29365 study (clinicaltrials.gov 02257567), the safety and efficacy of polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) versus bendamustine and rituximab (BR) alone, and polatuzumab vedotin plus bendamustine and obinutuzumab (Pola-BG) as a single-arm cohort were evaluated in patients with R/R FL. Following the phase Ib safety run-in, patients were randomized 1:1 to receive Pola-BR or BR alone in the phase II stage; a separate non-randomized Pola-BG cohort was examined in the phase Ib/II expansion stage. Primary endpoints included safety and tolerability (phase Ib) and positron emission tomography complete response (PET-CR) rate by independent review committee (phase II). Overall, 112 patients were enrolled (phase Ib safety run-in: Pola-BR, N=6; phase II randomized cohort: Pola-BR, N=39; BR, N=41; phase Ib/II expansion cohort: Pola-BG, N=26). PET-CR rates were 66.7% (phase Ib safety run-in, Pola-BR); 69.2% (phase II randomized, Pola-BR); 63.4% (phase II randomized, BR); and 65.4% (phase Ib/II expansion Pola-BG). There was a higher occurrence of cytopenias with Pola-BR and Pola-BG than with BR; serious adverse events were more frequent with Pola-BR (61.4%) and Pola-BG (46.2%) than with BR (29.3%). Overall, this analysis does not demonstrate a benefit of adding Pola to BR or BG regimens for patients with R/R FL.
Subject(s)
Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal , Immunoconjugates , Lymphoma, Follicular , Lymphoma, Large B-Cell, Diffuse , Humans , Rituximab/adverse effects , Bendamustine Hydrochloride/adverse effects , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/etiology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Immunoconjugates/adverse effects , Lymphoma, Large B-Cell, Diffuse/etiologyABSTRACT
The treatment of patients with relapsed or refractory lymphoid neoplasms represents a significant clinical challenge. Here, we identify the pro-survival BCL-2 protein family member MCL-1 as a resistance factor for the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma (NHL) cell lines and primary NHL samples. Mechanistically, we show that the antibody-drug conjugate polatuzumab vedotin promotes MCL-1 degradation via the ubiquitin/proteasome system. This targeted MCL-1 antagonism, when combined with venetoclax and the anti-CD20 antibodies obinutuzumab or rituximab, results in tumor regressions in preclinical NHL models, which are sustained even off-treatment. In a Phase Ib clinical trial (NCT02611323) of heavily pre-treated patients with relapsed or refractory NHL, 25/33 (76%) patients with follicular lymphoma and 5/17 (29%) patients with diffuse large B-cell lymphoma achieved complete or partial responses with an acceptable safety profile when treated with the recommended Phase II dose of polatuzumab vedotin in combination with venetoclax and an anti-CD20 antibody.
Subject(s)
Immunoconjugates , Lymphoma, Non-Hodgkin , Humans , Myeloid Cell Leukemia Sequence 1 Protein/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/pathology , Rituximab/therapeutic use , Immunoconjugates/therapeutic useABSTRACT
Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have heterogeneous outcomes; durable remissions are infrequently observed with standard approaches. Circulating tumor DNA (ctDNA) assessment is a sensitive, potentially prognostic tool in this setting. We assessed baseline ctDNA to identify patients with R/R DLBCL at high risk of relapse after receiving polatuzumab vedotin and bendamustine plus rituximab (BR) or BR alone. Patients were transplant ineligible and had received ≥1 prior line of therapy. The ctDNA assay, based on a customized panel of recurrently mutated genes in DLBCL, measured mutant molecules per mL (MMPM) at baseline and end of treatment (EOT). Endpoints included progression-free survival (PFS) and overall survival (OS) in subgroups stratified by baseline ctDNA and log-fold change in ctDNA at EOT vs baseline. In biomarker-evaluable patients (n = 33), baseline ctDNA level correlated with serum lactate dehydrogenase (LDH) concentration, number of prior therapies, stage, and International Prognostic Index (IPI). After adjusting for number of prior therapies ≥2, IPI score ≥3, and LDH above the upper limit of normal, high (greater than median) baseline ctDNA MMPM was independently prognostic for shorter PFS (adjusted hazard ratio [HR], 0.18 [95% CI, 0.05-0.65]) and OS (adjusted HR, 0.20 [95% CI, 0.06-0.68]). In 23 patients with baseline and EOT samples, a significantly greater decrease in ctDNA MMPM was observed in patients with complete response (CR) (n = 13) than those without CR (n = 10); P = .0025. Baseline ctDNA assessment may identify patients at high risk of progression and should be further evaluated as a monitoring tool in R/R DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT02257567.
Subject(s)
Circulating Tumor DNA , Lymphoma, Large B-Cell, Diffuse , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bendamustine Hydrochloride/therapeutic use , Humans , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Neoplasm Recurrence, Local , Rituximab/therapeutic useABSTRACT
Polatuzumab vedotin plus bendamustine and rituximab (pola + BR) received regulatory approvals for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) based on primary results from the randomized arms of the GO29365 study. After the randomized phase, 106 additional patients received pola + BR in a single-arm extension cohort. We report updated results from the randomized arms and results of the extension cohort. In this phase 1b/2 study, patients with R/R DLBCL who were transplant ineligible received up to six 21-day cycles of pola + BR or BR. The primary end point of the randomized arms was the complete response (CR) rate at end of treatment. Primary objectives of the extension cohort were safety, pharmacokinetic profile, and efficacy of pola + BR. As of 7 July 2020, a total of 192 patients with R/R DLBCL were enrolled in the pola + BR cohort (n = 152 [safety run-in, n = 6; randomized, n = 40; extension cohort, n = 106]) or the BR cohort (n = 40). Significant survival benefit with pola + BR vs BR persisted in the randomized arms (median progression-free survival, 9.2 vs 3.7 months [hazard ratio, 0.39; 95% confidence interval, 0.23-0.66]; median overall survival, 12.4 vs 4.7 months [hazard ratio, 0.42; 95% confidence interval, 0.24-0.72]). In the extension cohort, the independent review committee-assessed objective response rate was 41.5%, and the CR rate was 38.7%; median independent review committee-assessed progression-free survival and overall survival were 6.6 months and 12.5 months, respectively. No new safety signals with pola + BR were identified. Pola + BR is an effective treatment option for patients with R/R DLBCL, with a well-characterized and manageable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02257567.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Immunoconjugates , Antibodies, Monoclonal , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bendamustine Hydrochloride/therapeutic use , Humans , Rituximab/therapeutic useABSTRACT
BACKGROUND: Obinutuzumab with polatuzumab vedotin or lenalidomide showed tolerability and activity in phase 1b/2 trials that recruited patients with relapsed or refractory follicular lymphoma. We aimed to examine whether the novel polatuzumab vedotin-obinutuzumab-lenalidomide (Pola-G-Len) combination might enhance antitumour response in patients with relapsed or refractory follicular lymphoma. METHODS: This multicentre, single-arm phase 1b/2 study tested Pola-G-Len in patients with relapsed or refractory follicular lymphoma, and polatuzumab vedotin in combination with rituximab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Here we report the results from the cohort of patients with follicular lymphoma. The trial was done in 18 cancer centres across three countries (Spain, UK, and USA). Patients (≥18 years old) with CD20-positive relapsed or refractory follicular lymphoma (excluding grade 3b) and Eastern Cooperative Oncology Group performance status of 2 or less who had previously received anti-CD20-containing chemotherapy were eligible for inclusion. During the dose-escalation phase, patients received six 28-day cycles of induction treatment with intravenous obinutuzumab 1000 mg (all cohorts), and intravenous polatuzumab vedotin and oral lenalidomide (Celgene, Summit, NJ, USA) in the following doses: 1·4 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 1); 1·8 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 2); 1·4 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 3); 1·8 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 4); 1·4 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 5); and 1·8 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 6). Polatuzumab vedotin was administered on day 1, lenalidomide on days 1-21, and obinutuzumab on days 1, 8, and 15 of cycle one and day 1 of cycles two to six of each 28-day cycle. During phase 2 (dose expansion phase), patients received six cycles of induction with Pola-G-Len at the recommended phase 2 dose established during dose-escalation. Patients who had a response or stable disease at the end of induction were eligible to enter the maintenance phase, in which they received obinutuzumab for 24 months at 1000 mg on day 1 of every other 28-day cycle for a total of 12 doses, and lenalidomide for 12 months at 10 mg on days 1-21 of each 28-day cycle for a maximum of 12 cycles. The primary activity endpoint was complete response at the end of induction. Adverse events were monitored throughout the study. The primary safety objective was to determine the maximum tolerated dose of Pola-G-Len. Analyses were in the safety population, which included all patients that received at least one dose of any of the component drugs (ie, all patients who entered the induction phases in both the escalation and expansion phases), and activity-evaluable population, which included all patients who received at least one dose of any of the component drugs at the recommended phase 2 dose (ie, all patients who received the recommended phase 2 dose in the dose escalation investigation and all patients who entered induction in the dose expansion investigation). This ongoing trial is registered at ClinicalTrials.gov, NCT02600897. FINDINGS: Between March 24, 2016, and August 23, 2018, 56 patients (33 [59%] men and 23 [41%] women; 49 [88%] non-Hispanic or Latino) were enrolled. Two of four patients in cohort 2 reported dose-limiting toxicity events during dose escalation (one patient had grade 4 amylase and lipase elevation and one patient had grade 4 neutropenia and grade 3 thrombocytopenia), and there were no dose-limiting toxicities observed in cohorts 3 or 5; therefore, the recommended phase 2 dose for the dose-expansion was 1·4 mg/kg polatuzumab vedotin plus 20 mg lenalidomide. 46 (82%) patients were included in the activity-evaluable population. After a median follow up of 26·7 months (IQR 22·2-31·3) the objective response rate was 76% (90% CI 64-86) and complete response rate was 63% (90 CI 50-75). After a median follow-up of 27·0 months (IQR 18·7-34·0), the most common grade 3-4 adverse events were neutropenia (31 [55%] of 56 patients) and thrombocytopenia (14 [25%] patients). 61 serious adverse events were reported in 35 (63%) patients; the most common of which were febrile neutropenia (five [9%] patients; a sixth patient had febrile neutropenia, but this was not considered serious by the investigator), pneumonia (four [7%] patients), and pyrexia (four [7%] patients). One fatal adverse event (grade 5 septic shock) occurred in a patient who had discontinued study treatment due to disease progression and had initiated a new anti-lymphoma tyrosine kinase inhibitor treatment. This was not considered related to study treatment by the investigator. INTERPRETATION: Pola-G-Len showed high complete response rates, although it did not reached the prespecified threshold for activity, in patients who were heavily pretreated with refractory follicular lymphoma. Our findings compare favourably with available therapies and support future investigation of Pola-G-Len in a larger patient population. FUNDING: Genentech/F Hoffmann-La Roche.
Subject(s)
Lymphoma, Follicular , Adolescent , Adult , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Humans , Immunoconjugates , Lenalidomide/therapeutic use , Lymphoma, Follicular/drug therapy , Male , Neoplasm Recurrence, Local/drug therapy , Treatment OutcomeABSTRACT
BACKGROUND: Without prophylaxis, Pneumocystis jiroveci pneumonia (PCP) develops in 5%-15% of pediatric hematopoietic stem cell transplant (HCT) patients with mortality above 50%. Trimethoprim-sulfamethoxazole is a standard PCP prophylaxis; pentamidine is frequently used as second-line prophylaxis because of trimethoprim-sulfamethoxazole's potential for cytopenias. Monthly intravenous (IV) pentamidine has variable efficacy with PCP infection rates of 0%-10% in pediatric patients, and higher breakthrough rates in those younger than 2 years. We hypothesized that bimonthly (twice monthly) pentamidine might have equivalent safety and improved efficacy; therefore, we conducted a retrospective analysis of bimonthly pentamidine PCP prophylaxis. METHODS: We retrospectively reviewed records of all pediatric HCT patients who received bimonthly IV pentamidine between December 2006 and June 2013, and collected data regarding demographics, clinical course, prophylaxis rationale, laboratory values and adverse events. RESULTS: Between December 2006 and June 2013, 111 pediatric HCT patients received bimonthly IV pentamidine (574 doses, 8758 patient-days); 31 patients were younger than 2 years at initiation. In the majority (53% of courses), pentamidine was initiated because of cytopenias. Fourteen patients (12.6% of patients, 2.4% of doses) experienced a side-effect prompting discontinuation, including 3 patients with infusion-related hypotension/anaphylaxis and 3 with acute pancreatic dysfunction. No patients [0% (95% confidence interval: 0-3.2)] developed PCP during or after bimonthly IV pentamidine prophylaxis. CONCLUSIONS: Bimonthly IV pentamidine for PCP prophylaxis in the HCT pediatric population has comparable safety to monthly IV pentamidine and was highly effective, including in the very young. Bimonthly IV pentamidine should be considered in pediatric patients as second-line PCP prophylaxis.
Subject(s)
Antifungal Agents/administration & dosage , Chemoprevention/methods , Hematopoietic Stem Cell Transplantation/adverse effects , Pentamidine/administration & dosage , Pneumonia, Pneumocystis/prevention & control , Administration, Intravenous , Antifungal Agents/adverse effects , Chemoprevention/adverse effects , Child , Child, Preschool , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Humans , Infant , Male , Pentamidine/adverse effects , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation. PATIENTS AND METHODS: Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. RESULTS: Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02). CONCLUSIONS: When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.
Subject(s)
Busulfan/pharmacokinetics , Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/pharmacokinetics , Models, Biological , Adolescent , Age Factors , Algorithms , Busulfan/administration & dosage , Child , Child, Preschool , Female , Humans , Immunosuppressive Agents/administration & dosage , Infant , Male , Nonlinear Dynamics , Precision Medicine , Retrospective Studies , Young AdultABSTRACT
For children receiving allogeneic hematopoietic stem cell transplants (HSCTs), the toxicity of the conditioning regimen and graft failure remain challenges. We previously reported that targeted i.v. busulfan, fludarabine, and rabbit anti-thymocyte globulin (rATG) decreased toxicity but had a graft failure rate of 21%. To improve the engraftment rate, we replaced ATG with alemtuzumab, a monoclonal Ab targeting CD52. Thirty-five children with malignant and nonmalignant diseases were enrolled in this phase II prospective study. Twelve children had HLA-matched related donors (MRDs), 16 had 10 of 10, and 7 had 9 of 10 HLA allele-matched unrelated donors (MUDs). Thirty-one of 34 evaluable patients (91%) achieved a durable engraftment. All 3 patients who rejected had a nonmalignant disease and received a MUD transplantation (2 mismatched at 1 antigen). Three patients died of a transplantation-related complication (9% ± 5.2%). Seven patients had disease relapse or progression, 2 of whom died. At a median follow-up of 35 months (range, 15-85 months), the event-free survival (EFS) was 61% ± 9.0% and the overall survival (OS) was 78% ± 7.5%. The median time to neutrophil recovery, B cell, and T cell reconstitution were 16 days, 3 months, and 6 months, respectively. At 1 year, the median donor chimerism in whole blood, CD3, CD14/15, and CD19 subsets were 97%, 87%, 100%, and 99%, respectively. Six patients (17% ± 6.6%) developed acute graft-versus-host disease (aGVHD), only 2 of which were >grade II. Two patients (8% ± 5.4%) progressed to chronic GVHD (cGVHD). These results suggest that replacement of rATG with alemtuzumab may improve engraftment as well as decrease cGVHD rates without resulting in delays in immune reconstitution.