This study aims to provide a detailed analysis of allogeneic stem cell transplantation (allo-SCT) outcomes in a large T-cell acute lymphoblastic leukemia (T-ALL) cohort with a specific emphasis on the effects of pre-transplant minimal residual disease (MRD) and disease subtype, including the aggressive early-thymic precursor (ETP) subtype. Data from 102 allo-SCT patients with a diagnosis of T-ALL from three centers were retrospectively analyzed. Patients were grouped into four T-ALL subtypes: ETP, early, cortical and mature. At 3 years, overall survival (OS), PFS, non-relapse mortality and cumulative incidence (CI) progression were 35, 33, 11 and 55%, respectively. Patients transplanted in first complete remission (CR1) had a 3-year OS of 62% versus those transplanted in CR2 or greater (24%) (hazards ratio 1.6, P=0.2). Patients with MRD positivity at the time of transplant had significantly higher rates of progression compared with those with MRD negativity (76 vs 34%, hazards ratio 2.8, P=0.006). There was no difference in OS, PFS or cumulative incidence (CI) progression between disease subtypes, including ETP (n=16). ETP patients transplanted in CR1 (n=10) had OS of 47%, comparable to other disease subtypes, suggesting that allo-SCT can overcome the poor prognosis associated with ETP. MRD status at transplant was highly predictive of disease relapse, suggesting novel therapies are necessary to improve transplant outcomes.
T-cell acute lymphoblastic leukemia (T-ALL) represents ~20–25% of all cases of ALL diagnoses per year.1 Given the rarity of T-ALL, patients are typically treated in a similar fashion to B-cell (B-ALL) with dose-intense, multi-agent chemotherapy regimens.2, 3, 4 The largest cohort of T-ALL patients studied to date was in the MRC UKALL XII/ECOG E2993 international ALL trial.5 In this cohort of patients, 356 adult patients younger than 60 years of age were treated with intensive chemotherapy. Patients with a sibling donor in complete remission (CR) proceeded to allogeneic stem cell transplantation (allo-SCT) and had improved 5-year overall survival (OS) versus those without a donor (61 vs 46%, P=0.02) owing to lower relapse rates (25 vs 51%, P <0.001).6 Although the MRC trial suggested there may be an OS benefit to allo-SCT from a sibling donor in first remission; increasingly, allo-SCT is utilized primarily for high-risk disease subtypes such as early-thymic precursor T-ALL (ETP-ALL) ALL, or minimal residual disease (MRD) positivity after induction.
There are few transplant-specific studies, with an in-depth evaluation of conditioning and impact of prognostic factors, to guide the transplant management of T-ALL. The largest published report on transplant-specific outcomes in T-ALL is from Saudi Arabia, in which 53 patients received allo-SCT. OS was 43.5%, and patients in first remission (CR1) had improved OS versus those in second remission (CR2) (53.5 vs 31.9%).7 A large study from the EBMT in abstract form suggested patients transplanted in CR1 rather than CR2 and above, and those transplanted with TBI-based conditioning instead of non-TBI (chemotherapy)-based conditioning had improved outcomes, though data from this study are limited.8 An abstract by Hoelzer et al.9 suggested a benefit of allo-SCT for patients in CR1 with specific disease subtypes including early (CD1aneg sCD3−), and mature (CD1aneg sCD3+) T-ALL, though these results were not statistically validated. In addition, MRD and complete immune-phenotyping data, particularly as it relates to ETP-ALL are not available in these studies. Recently, a report by Dhedin et al.10 demonstrated that allo-SCT improved relapse-free survival versus chemotherapy alone in patients with ALL who had MRD>10−3 after induction, suggesting MRD positivity should be the primary determining factor for proceeding with allo-SCT in first remission.
MRD after therapy is well established as a risk factor for relapse in ALL,11, 12, 13 and subsequent studies have demonstrated that the presence of MRD resulted in impaired PFS in T-ALL.14, 15 There are few large studies outside of the pediatric literature, which have addressed the potential of MRD detection immediately pre-transplant as a predictor of impaired outcomes in T-ALL. One study with predominantly B-ALL demonstrated a trend toward worse PFS in patients with MRD by flow cytometry at time of transplant, though this was not conclusive due to low patient numbers.16 A second study with 160 patients (only 24 T-ALL) demonstrated increased risk of relapse in patients with MRD positivity prior to myeloablative conditioning (MAC) SCT with 3-year relapse-free survival of 61% in MRD-negative versus 34% in MRD-positive patients.17
T-ALL subtype has also been associated with chemotherapy outcomes. In the MRC study, CD1a-negative T-ALL was associated with higher rates of relapse and death compared to CD1a+ (cortical-type) disease (OS 64 vs 39%), though the effect of other subtypes is unknown. In other studies, the highest-risk subtype identified is ETP-ALL, which is a precursor T-ALL that expresses myeloid and/or immature markers. This subtype of T-ALL was found to have a 72% risk of relapse when first identified by St Jude investigators, and similar findings were subsequently confirmed in the UK.18, 19 Although recent evidence in children and young adults suggests that ETP may be a more intermediate-risk subtype, particularly when treated with an intensive consolidation/maintenance strategy with nelarabine, a recent analysis from MD Anderson by Jain et al.21 reported poor outcomes for adult patients with ETP, with median survival of only 20 months with chemotherapy alone.15,20 Whether allo-SCT can overcome the poor risk associated with ETP is unknown. For patients who do relapse with T-ALL, results are poor, with long-term survival of 7% seen in the MRC study, and 11% with the novel agent nelarabine without transplantation.22, 23
Here, we present the results of a multi-center analysis of 102 patients who received allo-SCT for T-ALL. This study aims to provide detailed transplant outcomes in a large T-ALL cohort of patients with a specific emphasis on the effects of pre-transplant MRD, subtype, including ETP and other prognostic markers on outcomes for patients receiving allo-SCT.
Materials and methods
Data were collected from three institutions including: University of Texas MD Anderson Cancer Center (UTMDACC), Oregon Health and Science University (OHSU), and National University Cancer Institute of Singapore. All patients with a diagnosis of T-ALL who received a first allo-SCT after 1 January 2000 to 1 January 2015 were included in the analysis. Patients with T-cell lymphoblastic lymphoma, defined as primarily nodal involvement with <25% bone marrow involvement, mixed-lineage ALL, bi-phenotypic leukemia, or human T-cell lymphotrophic virus (HTLV) positive adult T-cell leukemia/lymphoma were excluded. Patients who underwent ex vivo T-cell depleted allo-SCT were excluded. This study was approved by the institutional review board at each institution.
The indication to proceed with SCT and specific type of SCT was determined by the individual transplant physician based upon disease-related and transplant-related considerations. In general, patients with primary induction failure (PIF), and relapsed disease proceeded to allo-SCT. For patients in CR1, patients in earlier years proceeded to SCT if they had a matched-sibling donor, or a CR after PIF. In later years, the presence of MRD after induction or ETP-ALL subtype were indications for SCT. Most patients were younger, fit patients, and were eligible for MAC. Patients eligible for reduced-intensity conditioning (RIC) were typically older patients (depending on the center and time period, age 65+ or 70+), or patients with multiple co-morbidities, infections or impaired performance status. Alternative donor transplants were utilized if patients did not have a matched unrelated or related donor.
Flow cytometry immunophenotyping (FCI) data were collected from pathology reports, FCI reports, and primary flow cytometry data and evaluated centrally by JEB and JLJ. Pathology data were reviewed upon diagnosis when available, and upon relapse if no reports were available upon diagnosis. All patients had a diagnosis of T-ALL as outlined by WHO criteria.24 T-ALL subtypes were determined utilizing a modified WHO/EGIL scheme initially developed by Hoelzer et al.,9into Pre-T, Pro-T, mature (medullary) and cortical (thymic) subtypes (Table 1).24, 25 For these cases, attempting to apply criteria based on expression patterns of CD4 and CD8 left many cases unclassifiable, and therefore these markers were not used in this classification scheme. As initial analysis showed that the outcomes of Pro-T and Pre-T were the same, this group was then combined into an ‘Early’ T-ALL subtype for the purpose of further analysis. ETP was classified as: CD1aneg, cytoplasmic CD3+, CD8−, T-ALL, with <75% expression of CD5, and the presence of one or more myeloid markers on at least 25% of lymphoblasts including: CD117, CD34, HLA-DR, CD13, CD33, CD11b and/or CD65.18
MRD was defined as the presence of T-ALL on FCI on bone marrow biopsy within 1 month prior to allo-SCT. Patients entering transplant with aplasia or with active disease were not considered to have MRD. Given detection of MRD by flow cytometry became routine by 2004, for the purpose of MRD analysis, only patients who received transplantation after 1 January 2004 were considered.
MRD was assessed utilizing multi-parameter FCI with a sensitivity of 0.01% at UTMDACC and OHSU, and sensitivity of 0.04% at National University Cancer Institute of Singapore. Bone marrow aspirate samples of 200 000 nucleated bone marrow cells were analyzed using a panel of markers including: CD1a, CD2, cytoplasmic CD3, surface CD3, CD4, CD5, CD7, CD8, CD10, CD13, CD33, CD34, CD45, CD56, HLA-DR and terminal deoxynucleotidyl transferase. For most cases, cytoplasmic CD3 staining was used for gating, and surface CD3 was used to identify immature (CD3-negative) cells. Starting in 2012, cases at UTMDACC were analyzed with initial gating on CD7+CD45 dim+ cells. MRD was considered positive if a cluster of at least 20 cells was present on bivariate dot plots, with a significant difference in expression (greater than or equal to threefold) of two or greater Ags, compared with the known phenotype of mature marrow T and natural killer cells was present. MRD was reported as a fraction of total nucleated bone marrow cells. Each center certified their process and level of detection of MRD, with a level detection in the order of 10−3 (0.01%). All centers were academic transplant centers, with frequent utilization of MRD assessments in the transplant and non-transplant setting. When evaluating MRD as a prognostic marker, patients not in CR were omitted from MRD analysis.
The primary objective of the analysis was to compare outcomes according to T-ALL subtype. OS and PFS were estimated using the Kaplan–Meier method. Overall survival was estimated from the date of transplant until death from any cause, and PFS was estimated from the date of transplant until disease progression or death from any cause. The rate of disease progression, non-relapse mortality (NRM), acute GVHD and chronic GVHD was estimated using the cumulative incidence (CI) method to account for competing risks. NRM was defined as death before disease progression and in the absence of persistent disease. NRM was considered a competing risk for disease progression; disease progression or death with persistent disease were considered competing risks for NRM, and disease progression or death from any cause before the development of GVHD were considered competing risks for GVHD. Acute GVHD was graded on the Glucksberg scale from grade I-IV, whereas chronic GVHD was graded as extensive/limited.26, 27 Cox Proportional Hazards regression was used on univariate and multivariate analysis to assess predictors of disease progression. Reference for regression analysis was determined either based upon known prognostic factors, or if unknown, by convention the group with the highest number was used as the reference group. Patients with missing data for a particular risk factor were excluded from the risk factors analysis. High-risk cytogenetics were defined according to the scheme developed by Pullarkat et al.28 Because MRD data became systematically available after 2003, the impact of MRD on disease progression was evaluated in a subset analysis including patients transplanted starting January 2004 (N=84). Statistical significance was defined at the 0.05 level. Statistical analyses were primarily performed using STATA 11.0 (StataCorp. 2009. Stata Statistical Software: Release 11. College Station, TX, USA: StataCorp LP).
One hundred and two patients received first allo-SCT for T-ALL between 1 January 2000 and 1 January 2015. The median age at transplant was 31 years (range 2–72 years), the median number of chemotherapy cycles prior to allo-SCT was 2 (range 1–8) and median follow-up time in alive patients was 2.9 years (range 0.3–11 years).
Seventy-two patients had data regarding induction therapy. In this group of patients, 51 patients (71%) received Hyper-CVAD based therapy, of which 10 (14%) received Hyper-CVAD plus nelarabine. Two patients received Berlin-Frankfurt-Munster (BFM), 2 cytarabine only and 17 received other combinations for induction. Of 51 patients for whom salvage chemotherapy data were available, the median number of salvage chemotherapy regimens prior to transplant was 1 (range 1–5). Of these patients, 8 (16%) received nelarabine.
Only 37% of patients were in CR1 at the time of allo-SCT and 14% had high-risk cytogenetics/complex karyotype. The majority of patients received MAC (77%). The most common MAC regimen was etoposide or cyclophosphamide/12 Gy TBI (52%), followed by busulfan/clofarabine ± Thiotepa (24%), busulfan/melphalan (11%), busulfan/fludarabine ± clofarabine (6%), busulfan/cyclophosphamide ± Thiotepa (3%), carmustine/etoposide/cytarabine/melphalan (BEAM)/alemtuzumab (3%), and fludarabine/9.9 Gy TBI (1%). There was no statistically significant difference between OS or PFS between patients who received MAC versus RIC/NMA conditioning (P=0.8, 0.9, respectively). Patient characteristics are provided in Table 2, and transplant characteristics are presented in Table 3.
There was no statistically significant difference in survival outcomes between the three centers, with 3-year PFS of 33% at UTMDACC (used as reference for PFS), 38% at OHSU (P=0.6) and 26% at National University Cancer Institute of Singapore (P=0.6). Among the entire cohort of 102 patients, the 3-year OS and PFS was 35 and 33%, respectively. The CI of NRM was 5% at 100 days, 10% at 1 year and 11% at 3 years. For patients transplanted in CR1, the actuarial OS and PFS were 60 and 58%, respectively (Supplementary Figures 1 and 2). Progression was the primary cause of treatment failure, and the CI progression was 44% at 1 year and 55% at 3 years. (Figure 1). The CI grade II–IV and III–IV acute GVHD was 22 and 18%, respectively, at day 100 and the CI chronic GVHD was 32% at 3 years.
T-ALL subtype analysis
T-ALL subtype was determined in 88 patients (86%) who had available FCI data. There was no difference in OS between the Pro-T and Pre-T-ALL groups (47 vs 31%, P=0.57) so they were considered together as ‘Early T-ALL’. At 3 years, there was no difference in OS, PFS or CI Progression according to T-ALL subtypes, including ETP. (Figure 2a, Supplementary Table 1) OS for all patients with ETP was 29%, with a 63% rate of progression at 3 years. However, when patients with ETP underwent allo-SCT in CR1, OS was 47% at 3 years, which was not statistically significant from all other disease subtypes (63%), P=0.5 (Figure 2b, Supplementary Table 2).
MRD and univariate risk factor analysis
Given NRM was low, and progression was the primary cause of treatment failure, risk factors for disease progression were evaluated. On univariate analysis for progression, there was no difference in progression rates according to institution, age, hematopoietic cell transplantation-co-morbidity index, white blood count, presence of extra-medullary disease at diagnosis, presence of CNS involvement at diagnosis, stem cell source, donor type, TBI>2 Gy, conditioning intensity, age at transplantation (⩽18 vs 18 and above), high risk/complex cytogenetics (Southwest Oncology Group (SWOG) classification scheme), or use of ATG.28 (Table 4) T-ALL subtype, including ETP, was not prognostic for progression, though the mature subtype was borderline significant with a wide confidence interval (hazards ratio 2.3 1.01–5.2, P=0.05), even though there was no difference in OS for the mature subset (Table 4, Supplementary Table 1). Patients in CR2+ at transplant trended toward increased risk for progression, whereas patients with PIF/CR1 and no CR had increased risk of progression. (Table 4). With a median follow-up time of 2 years, the actuarial OS for patients who were in CR1, CR2+, PIF/CRI and no CR were 60, 24, 33 and 0%, respectively. In addition, MRD positivity at transplant was associated with increased risk of progression. CI progression was 45% at 1 year and 76% at 3 years in patients who were MRD positive at the time of transplant (Figure 3). MRD status was considered for the purpose of analysis whether in CR1, CR2+ or PIF/CR1 given low patient numbers. Supplementary Table 3 provides a description of outcomes based upon remission status and MRD status at the time of transplant. Given the potential heterogeneity across institutions in terms of monitoring MRD, we did a univariate evaluation of MRD assessment only among MDACC patients. In this analysis, MRD positivity at transplant remained a negative prognostic factor for disease progression (hazards ratio 2.3:1–5.3, P=0.049).
CR status and MRD status were highly correlated variables, so each variable was evaluated independently. On multivariate analysis only MRD status and disease status (CR1/PIF and No CR), were predictive of increased risk of progression. (Table 5) Even when CR status and MRD status were taken into account, ETP was not a statistically significant predictor for progression in either of two models (Table 5).
Herein we present one of the largest series of T-ALL patients undergoing allo-SCT with detailed analyses of disease status, MRD, histology/immune phenotyping, including ETP-ALL, and transplant preparative regimens.
Our analysis demonstrated no difference in allo-SCT outcomes between the disease subtypes, including ETP-ALL. ETP-ALL is associated with increased risk of relapse and death, particularly in the adult population when treated with chemotherapy alone, with a median OS of 20 months in the UTMDACC analysis.21 The study preseted by Wood et al.15 only in abstract form, suggested that children and young adults treated with a standardized, intensive course of nelarabine, can overcome the poor prognosis associated with ETP-ALL. However, given many adults may have difficulty tolerating an intensive course of nelarabine, consolidation with allo-SCT is indicated for this patient population and was the conclusion of the study by Jain et al. In the present analysis, patients who received allo-SCT for ETP-ALL in CR1 had OS and PFS of 47 and 42%, respectively, suggesting that allo-SCT can abrogate the negative prognostic impact of ETP-ALL. Although the numbers of patients with ETP-ALL in CR1 (n=10) are low, given the rarity of ETP-ALL, it is unlikely that large studies in adult patients will be undertaken looking into this question. Therefore, when taken in context with the results reported by Jain et al., our data suggest that strong consideration should be given for allo-SCT in patients with ETP-ALL after attainment of first remission unless treated with a specific intensive chemotherapy regimen which has been shown to decrease relapse in ETP-ALL. For patients with non-ETP T-ALL, patients should proceed to allo-SCT based upon other prognostic factors such as MRD at the end of induction therapy, as disease subtype does not appear to effect transplantation outcomes (Figure 2).
The presence of MRD at the end of induction therapy is a clear prognostic marker for increased disease relapse, and is considered a standard indication for allo-SCT, even for patients in CR1.13, 14, 15 Increasing data in adult ALL corroborates the pediatric literature that MRD status immediately prior to allo-SCT predicts for poor transplant outcomes. However, the majority of studies are in patients with B-ALL and small numbers of T-ALL patients.16, 17, 29 Here we report a strong correlation between the presence of MRD at the time of transplant, and increased risk of disease progression (78% MRD+ vs 31% MRD-, hazards ratio 2.6 (1.3–5.4), P=0.01), in patients with T-ALL. Indeed, patients in CR1 with MRD at the time of transplant had similar outcomes to those transplanted in CR2+ (PFS 33% at 3 years, Supplementary Table 3). This suggests that MRD positivity by flow cytometry immediately prior to allo-SCT, regardless of remission status, is predictive of relapse post allo-SCT in T-ALL. However, despite the strong correlation of MRD with risk of disease progression, owing to low numbers of MRD-positive patients, we could not definitively determine the effect of remission status on MRD. Although some patients will be cured with allo-SCT even with MRD positivity immediately prior to transplant, these data suggest a possible benefit for MRD-positive patients from additional therapy or novel therapies either pre-transplant to induce MRD negativity, or post-transplant to prevent disease relapse. In addition, given the sensitivity of MRD testing by flow cytometry has changed over time and can vary by center, these results should be interpreted with caution and the results may not be generalizable to current flow assays with higher degrees of sensitivity or for patients undergoing molecular testing by PCR.
Given the large number of patients available for analysis, we also evaluated the impact of other prognostic factors on transplant outcomes in T-ALL. Although no firm conclusions can be made from this cohort given the heterogeneity of conditioning regimens, several interesting findings from this study can help guide decision making for patients proceeding to allo-SCT for T-ALL. Conditioning chemotherapy in ALL has been historically with MAC TBI-based regimens (etoposide or cyclophosphamide), and this remains the standard of care in many institutions. Indeed, a registry analysis from the EBMT presented in abstract form suggested TBI may have a protective effect in T-ALL; however, details of this study are not yet available.8 Alternatively, we found no difference in progression rates between TBI-based, or busulfan-based conditioning, either among all patients, or patients with extra-medullary disease, who had a trend toward higher progression on univariate analysis (Table 4). Therefore, busulfan-based conditioning regimens may be an acceptable alternative to TBI-based conditioning in T-ALL. This specific question is being investigated by the Leukemia working group of the Center for International Bone Marrow Transplant Research. Although the majority of patients (79%) received MAC conditioning, we did not see any difference in outcomes in patients receiving RIC/NMA conditioning, including cord blood transplants. Although MAC conditioning is preferred given the aggressive nature of T-ALL, RIC (particularly Flu/Mel based) may be an acceptable alternative for those who cannot tolerate MAC conditioning. A report from the EBMT has also suggested acceptable results utilizing RIC versus MAC in T-ALL, and a recent study from Seattle suggested that patients with MRD negativity in CR2+ may benefit from a RIC allo-SCT.29, 30 The present study analyzed only allo-SCT outcomes for T-ALL, though autologous SCT may have a role in consolidation therapy post transplantation in certain subsets of patients as discussed in recent papers.31, 32
Remission status was a clear prognostic indicator for progression and treatment failure. Patients with delayed remission (PIF/CR1), and particularly patients transplanted with active disease, had poor outcomes. All patients in the PIF/CR1 group had MRD at the time of transplantation, which was likely the primary driver of poor outcomes, though this analysis is limited to low numbers. For this group of patients, post-transplant therapy, such as maintenance therapy may help to improve outcomes. Novel agents and approaches are necessary for those patients not in remission prior to allo-SCT given poor long-term outcomes in this group of patients. There was a trend (hazards ratio 1.6, P=0.2) for increased risk of progression for those transplanted in CR2+ vs CR1, though this did not reach statistical significance. Our data suggest that patients in CR1 with MRD or ETP-ALL should proceed with allo-SCT. In keeping with this recommendation, improved outcomes were noted in a recent paper by Dhedin et al.10 for patients transplanted in CR1 who were MRD positive.
Our study has several limitations. It is a retrospective analysis, and although FCI data were reviewed centrally, primary flow cytometry data were not available for all patients. In addition, the relative numbers of patients in each disease subtype, with and without MRD, or other risk factors is relatively small, thus broad conclusions cannot be made. Despite similar procedures for detecting MRD across institutions, MRD detection is not standardized across institutions, which could confound the data. Data on recently described genetic mutations, such as NOTCH1/FBXW7, which have been associated with favorable outcomes in T-ALL, are unknown as these data were not routinely collected during the study period.33, 34 Furthermore, data on pre-transplant chemotherapy regimens, information regarding time from diagnosis to transplant and the number of patients with similar diagnoses treated across the institutions were limited. Furthermore, there was significant heterogeneity of conditioning regimens. Nevertheless, the correlation of MRD with progression was strong, and is in keeping with prior studies in the non-transplant setting. In addition, the lack of impact of disease subtype on T-ALL patient outcomes is consistent with the data by Jain et al., with the exception that ETP outcomes are better with allo-SCT. Finally, despite the limitations posed by the retrospective nature of this analysis, we present the largest, most detailed analysis of T-ALL allo-SCT outcomes to date which may inform future T-ALL studies in allo-SCT, and help guide treatment decisions for the rare ETP-ALL subtype. Ultimately, a large registry analysis will be needed to corroborate these findings.
Here we present the largest and most-detailed analysis of allo-SCT outcomes in T-ALL to date. Patients with ETP-ALL had long-term survival equivalent to other disease subtypes, suggesting that allo-SCT can overcome the poor prognosis associated with ETP-ALL, particularly when performed in first remission. There was no difference in outcomes between patients treated with TBI-based versus busulfan-based conditioning, suggesting TBI may not be necessary to achieve cure in T-ALL. MRD status at transplant was highly predictive of disease relapse, suggesting novel therapies before or post-SCT are necessary to improve transplant outcomes in this subset of patients.
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We acknowledge William Dibb for his contributions to data collection and Guang Fan for her contributions regarding pathology data from OHSU. The authors have no source of income for this study to declare.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website
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Brammer, J., Saliba, R., Jorgensen, J. et al. Multi-center analysis of the effect of T-cell acute lymphoblastic leukemia subtype and minimal residual disease on allogeneic stem cell transplantation outcomes. Bone Marrow Transplant 52, 20–27 (2017). https://doi.org/10.1038/bmt.2016.194
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