
==== Front
Blood Adv
Blood Adv
Blood Advances
2473-9529
2473-9537
The American Society of Hematology

S2473-9529(24)00350-1
10.1182/bloodadvances.2023012497
Clinical Trials and Observations
Yttrium-90 anti-CD25 BEAM conditioning for autologous hematopoietic cell transplantation in Peripheral T-cell lymphoma
Zain Jasmine jazain@coh.org
1∗
Tsai Ni-Chun 2
Palmer Joycelynne 12
Simpson Jennifer 3
Adhikarla Vikram 2
Bading James R. 4
Yazaki Paul 4
Smith Eileen P. 1
Dandapani Savita 5
Song Joo Y. 6
Karras Nicole A. 7
Herrera Alex F. 1
Salhotra Amandeep 1
Nademanee Auayporn P. 1
Nakamura Ryotaro 1
Smith D. Lynne 1
Yamauchi David 8
Poku Erasmus K. 9
Biglang-Awa V. Eric 9
Colcher David 4
Shively John E. 4
Wu Anna M. 4
Forman Stephen J. 1
Wong Jeffrey 5
Thomas Sandra 1
1 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
2 Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Duarte, CA
3 Clinical Trials Office, City of Hope National Medical Center, Duarte, CA
4 Department of Immunology and Theranostics, City of Hope National Medical Center, Duarte, CA
5 Department of Radiology, City of Hope National Medical Center, Duarte, CA
6 Department of Pathology, City of Hope National Medical Center, Duarte, CA
7 Department of Pediatrics, City of Hope National Medical Center, Duarte, CA
8 Department of Diagnostic Radiology, City of Hope National Medical Center, Duarte, CA
9 Radiopharmacy, City of Hope National Medical Center, Duarte, CA
∗ Correspondence: Jasmine Zain, Hematology and Hematopoietic Cell Transplantation, City of Hope Hematology, 1500 E Duarte Rd, Duarte, CA 91010; jazain@coh.org
06 6 2024
24 9 2024
06 6 2024
8 18 48124822
27 12 2023
15 5 2024
© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
2024
The American Society of Hematology
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Key Points

• 90Y–anti-CD25 aTac BEAM AHCT was safe and tolerable in patients with relapsed/refractory PTCL.

• 90Y–anti-CD25 aTac BEAM AHCT was associated with encouraging outcomes in relapsed/refractory PTCL.

Visual Abstract

Abstract

Peripheral T-cell lymphomas (PTCLs) have a poor prognosis with current treatments. High-dose chemotherapy followed by autologous hematopoietic cell transplant (AHCT) is used as a consolidation strategy after achieving clinical remission with first-line therapy, as well as in chemotherapy-sensitive relapse if allogeneic transplant is not an option. CD25 is a targetable protein often highly expressed in PTCLs. In this phase 1 clinical trial, we tested the addition of β-emitting 90yttrium (90Y)–labeled chimeric anti-CD25 basiliximab (aTac) to BEAM (carmustine, etoposide, cytarabine, and melphalan) as conditioning for AHCT for patients with PTCL. Twenty-three AHCT-eligible patients were enrolled, and 20 received therapeutic 90Y-aTac-BEAM AHCT. Radiation doses of 0.4, 0.5, and 0.6 mCi/kg were tested. With no observed dose-limiting toxicities, 0.6 mCi/kg was deemed the recommended phase 2 dose. The most prevalent adverse effect, grade 2 mucositis, was experienced by 80% of patients. As of this report, 6 (30%) of the treated patients had died, 5 due to progressive disease and 1 due to multiple organ failure (median time of death, 17 months [range, 9-21]) after AHCT. Median follow-up was 24 months (range, 9-26) overall and 24 months (range, 13-26) for surviving patients. For patients who received therapeutic 90Y-aTac-BEAM AHCT, the 2-year progression-free and overall survival were 59% (95% confidence interval [CI], 34-77) and 68% (95% CI, 42-84), respectively. 90Y-aTac-BEAM appears to be safe as an AHCT conditioning regimen for PTCL, with no increased toxicity over the toxicities historically seen with BEAM alone in this patient population. This trial was registered at www.ClinicalTrials.gov as #NCT02342782.
==== Body
pmcIntroduction

Most systemic peripheral T-cell lymphomas (PTCLs) have poor prognosis with current therapies, an exception being anaplastic lymphoma kinase (ALK)–positive anaplastic large cell lymphomas (ALCLs) with low International Prognostic Index scores. Allogeneic stem cell transplantation is offered early in the disease course for very aggressive histologies (human T-lymphotropic virus type 1–associated acute T-cell lymphoma/leukemia, gamma delta T-cell lymphoma, and hepatosplenic T-cell lymphoma) preferably in first remission, or in other subtypes in cases of relapse or refractory disease. In the United States, the National Comprehensive Cancer Network guidelines recommend consideration of high-dose therapy and autologous hematopoietic cell transplant (AHCT) for patients with nodal T-cell lymphomas who achieve remission after initial induction therapy to improve outcomes.1,2 These recommendations are based on 5 prospective studies and many retrospective and meta-analyses that support that AHCT as consolidation is probably the most effective way to improve progression-free survival (PFS) and overall survival (OS) in PTCL.1, 2, 3, 4, 5, 6, 7 For relapsed disease, AHCT could be offered to patients with chemotherapy-sensitive relapse who did not receive AHCT in first remission. However, outcomes may be worse if AHCT is performed beyond complete remission after initial therapy (CR1).8 Most of these cases are referred for an allogeneic stem cell transplant, which has been shown to result in long term survival. In an analysis of Center for International Blood and Marrow Transplant Research (CIBMTR) data, the outcomes of allotransplantation in RR PTCL were reported as 3-year OS of up to 60%.9

The rarity and heterogenicity of T-cell lymphomas make meaningful clinical trials challenging. Most treatment paradigms are borrowed from studies of aggressive B-cell lymphomas. The most-used conditioning regimen for AHCT for lymphomas including PTCL is BEAM (bis-chloroethylnitrosourea [carmustine], etoposide, cytarabine, and melphalan],10 which lacks any agent directed specifically at malignant T cells and may be the cause of suboptimal outcomes. Recently targeted treatments in PTCL have been shown to improve outcomes11 and their incorporation into conditioning regimens would be expected to improve outcomes for patients with PTCL who receive AHCT.

CD25 (Tac), forms 1 component of the high-affinity heterotrimeric interleukin-2 receptor, and is expressed in 40% to 50% of PTCL specimens.12 CD25 is also expressed in activated T cells, regulatory T cells, and tumor infiltrating lymphocytes, which populate the tumor microenvironment and may exert immunosuppressive effects.13 Interleukin-2–mediated signaling via CD25 leads to proliferation and survival of malignant cells through the JAK/STAT5, PI3K/Akt/mTOR and mitogen-activated protein kinase pathways.14 Thus, disruption of CD25 is an attractive therapeutic strategy that directly targets tumor cells while simultaneously modifying the tumor microenvironment by disrupting regulatory T cells.15, 16, 17, 18

The role of CD25 expression in the pathogenesis of PTCL remains unclear, but antibody-based therapy designed to target and disrupt CD25-mediated signaling (anti-Tac) has been attempted in the treatment of T-cell lymphomas.15, 16, 17, 18 The humanized anti-CD25 antibody daclizumab produced partial responses in patients with adult T-cell leukemia-lymphoma (ATLL) with the smoldering subtype.18 Denileukin diftitox (Ontak) is a CD25-directed immunotoxin with a diphtheria toxin payload, that has produced a response rate of 30 % in patients with relapsed cutaneous T-cell lymphomas (CTCL).16 This molecule was recently reengineered to have 1.5- to 2-times more bioactivity than denileukin diftitox and renamed E7777. It has shown activity in patients with relapsed/refractory CTCL whose tumors expressed CD25 (overall response rate of 36.2 %; duration of response, 6-12 months) in a multicenter open-label study.19 ADCT-301, which fuses pyrrolobenzodiazepine with the human immunoglobulin G1 anti-CD25 antibody, has been investigated in both Hodgkin lymphoma (HL) and PTCL. An initial phase 1 study included 22 patients with PTCL; responses were seen in 42% of cases.20

Radioimmunotherapy (RIT), in which antibodies are labeled with radioactive conjugates, enables targeted delivery of radiotherapy to tumors. Because of their radiosensitivity, lymphomas have been considered ideal targets for RIT, which has been shown to be safe and effective as a treatment for various lymphomas and has been incorporated into AHCT conditioning regimens.21, 22, 23, 24 Yttrium-90 (90Y)-labeled basiliximab (aTac) is a humanized monoclonal antibody designed to deliver targeted radiation to CD25-expressing malignant cells.25 In patients with relapsed ATLL, in which there is high expression of CD25 on malignant ATLL cells compared with normal resting T cells,26 90Y-labeled aTac administration resulted in responses in 9 of 16 (56%) of patients. The main toxicities were hematopoietic.26 More recent studies have sought to combine 90Y-labeled aTac with high-dose chemotherapy as part of conditioning regimens before AHCT with promising results and no major safety concerns.22,27 Additionally 131iodide-labeled basiliximab (CHT-25)25 and 90Y-daclizumab have been investigated in HL.28

Here, we report the results of a phase 1 trial evaluating 90Y-aTac with BEAM conditioning for AHCT in patients specifically with PTCL. We tested the hypothesis that using CD25-directed RIT as part of the AHCT regimen would be safe and incur much less radiation dose to nontumor tissues and organs than does total body irradiation (TBI). This will have the advantage of adding a targeted radiation to the “standard” conditioning regimen for PTCL and potentially make it more effective without incurring the toxic effects of TBI, which is associated with increased regimen-related toxicity as well as long-term risk of secondary malignancies.29,30

Methods

Patient eligibility

This was a single-center, phase 1, dose-escalation study of 90Y-aTac-BEAM for patients with PTCL undergoing AHCT. Eligible patients were aged ≥18 years with a diagnosis of mature T-cell non-HL as per World Health Organization 2008 classification,31 for whom AHCT was being considered as a therapeutic option. This included (1) patients who had achieved a CR1 and needed consolidation, and (2) relapsed patients without prior AHCT who had achieved either a partial response or CR after salvage therapy and for whom an allogeneic transplant was not an option. All histologies were allowed except CTCL and ALK-positive ALCL.

To be eligible for AHCT, patients had to meet the following institutionally mandated criteria: Karnofsky performance status of ≥70%; adequate organ function, including cardiac ejection fraction of ≥50% by echocardiogram or multigated acquisition scan; FEV1 of >65% of predicted measured, or DLCO of ≥50% of predicted measured; bilirubin of ≤1.5 the upper limit of normal, and aspartate aminotransferase and alanine aminotransferase of ≤2 × the upper limit of normal; and serum creatinine of ≤1.5 mg/dL, and measured creatinine clearance of ≥60 mL/min. Recovery from nonhematologic toxicities of salvage therapy to grade ≤2 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was required, as was collection by apheresis of at least 3.0 × 106 CD34 cells per kg of autologous hematopoietic progenitor cells from a maximum of 10 collections. Supplementation of apheresis by bone marrow harvest was not allowed.

Patients with progressive disease, HIV infection, active hepatitis B or C infection, or evidence of marrow disease by flow and morphology after upfront or salvage cytoreductive therapy and before stem cell mobilization were excluded. Additional exclusions included the following: myelodysplastic syndrome (MDS) or any known MDS–associated cytogenetic abnormality in the bone marrow; prior AHCT or allogeneic HCT; and significant external beam dose-limiting radiation to a critical organ, including >20 Gy to any portion of the lung, >5 Gy to any portion of the kidney, or any prior radiation to the heart.

All patients provided signed informed consent for participation in the clinical trial. The study was approved by the institutional review board and conducted in accordance with the principles of the Declaration of Helsinki, and was registered at www.ClinicalTrials.gov as #NCT02342782.

Radiolabeling, pharmacokinetics, biodistribution, dosimetry, and immunohistochemistry

The anti-CD25 monoclonal antibody basiliximab (5 mg per dose) was conjugated with 1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA), as previously described.22 Imaging doses prepared with indium-111 (111In-basiliximab/DOTA), and therapeutic doses prepared with yttrium-90 (90Y-basiliximab/DOTA) were purified and underwent quality control testing, as previously described.22 Administration was performed within 6 hours of radiolabeling.

Unlabeled (“cold”) basiliximab (5 mg) was administered intravenously 21 days before AHCT (ie, on “day –21”; Figure 1) to block circulating soluble CD25 antigen and thereby improve the pharmacokinetics and tumor targeting of radiolabeled basiliximab.22,26 Premedication (acetaminophen and diphenhydramine) and infusion of unlabeled basiliximab were as previously described.22 Soluble CD25 levels were determined from a blood draw before intravenous administration of cold basiliximab on day –21.Figure 1. Treatment schema and CONSORT diagram.

Blood clearance of 111In-basiliximab/DOTA and 90Y-basiliximab/DOTA was measured in peripheral venous samples drawn before cold dose, before hot dose, and 2 hours, 4 to 6 hours, 1 day, 2 days, 3 to 4 days, and 5 and 6 days after injection. Terminal elimination, serum half-life (t1/2), and area under the curve were determined as previously described.22

To assess biodistribution, 111In-basiliximab/DOTA (imaging dose 5 mCi) was administered on day –21. Whole-body planar scans were acquired at 2, 24, 48, 120, and 144 to 168 hours after injection. Single-photon emission computerized tomography (SPECT) images were also obtained at 48 and 72 to 120 hours after injection (Figure 1). To verify scanner sensitivity, a calibrated sample of 111In-basiliximab/DOTA was placed adjacent to patients’ legs. Radioactivity quantification was performed using the conjugate-view approach.32 Attenuation correction of the calculated region of interest activity was performed based on organ measurements from a computed tomography (CT) scan of the patient taken close in time to the 111In-basiliximab/DOTA scans. Red marrow dose was calculated from blood activity, and urine clearance was used to verify residual activity in the body (samples were collected daily for 6 days, starting on the day of infusion). Absorbed dose estimates were calculated using the standard adult human model in OLINDA/EXM.33 Biodistribution was determined from both visual and quantitative evaluation of the planar and SPECT images. Visual assessment was performed by the study radiologist (D.Y.). Altered biodistribution was defined as ≥1 of the following: (1) diffuse uptake in normal lung more intense than cardiac blood pool on the 2-hour time point images, or more intense than liver on the 24-hour or 48-hour time point images; (2) kidneys more intense than liver on the posterior view at 24 hour or 48 hours; (3) intense areas of uptake within normal bowel comparable with liver in the 24-hour or 48-hour images.

Study treatment and AHCT

The therapeutic 90Y-basiliximab/DOTA dose was administered on day –14 using the same protocol as on day –21. Three 90Y-basiliximab/DOTA dose levels were tested: 0.4, 0.5, and 0.6 mCi/kg. The maximum 90Y dose was set at 40 mCi for the 0.4 mCi/kg dose level, 50 mCi for the 0.5 mCi/kg dose level, and 60 mCi for the 0.6 mCi/kg dose level.

The BEAM conditioning regimen was administered according to institutional practice (Figure 1): bis-chloroethylnitrosourea on days −7 and −6, 150 mg/m2 IV based on adjusted ideal body weight; cytarabine and etoposide twice daily on days –5, –4, –3, and –2, each dose 100 mg/m2 based on adjusted ideal body weight; and melphalan 140 mg/m2 on day –1. Stem cells were infused on day 0, followed by 5 μg/kg per day of granulocyte colony-stimulating factor administered starting on day +5 and continued until absolute neutrophil count was >500 for 3 consecutive days. Supportive care (premedications, antiemetics, and infection prophylaxis) was given according to institutional practice.

Study assessments and end points

Safety was monitored continuously according to the CTCAE version 4.03 and the Bearman Toxicity scale.22 Dose-limiting toxicities (DLTs) were assessed from day –21 through day +30. DLTs were defined as any grade ≥3 toxicity according to the Bearman scale, grade 4 neutropenia lasting >42 days, any grade ≥4 infusion-related reaction, or any death unless clearly unrelated to study treatment. Pulmonary function tests and cardiac echocardiogram or multigated acquisition scan were performed on day +100 and 1 year after AHCT. Anti-basiliximab antibodies were assayed at day +100, day +180, and 1 year after AHCT, and post-RIT cytogenetic assessment was performed on day +100, day +180, 1 year, and 2 years after AHCT.

Response to treatment was evaluated according to the 2007 Revised Response Criteria for Malignant Lymphoma.34 Bone marrow biopsies for disease assessment were performed at day +100, day +180, 1 year, and 2 years after AHCT. Extent of disease was monitored by fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography/CT (FDG-PET/CT) scans performed before the first infusion of cold basiliximab (“baseline scan”) and at day +30, day +100, day +180, 1 year, 18 months, and 2 years after AHCT. After documentation of CR, either FDG-PET/CT or CT was allowed.

The primary end point was the safety and feasibility of 90Y-basiliximab/DOTA when given to patients with PTCL in combination with standard-dose BEAM as part of conditioning for AHCT. Secondary end points included 1-year and 2-year PFS, OS, nonrelapse mortality, and cumulative incidence of relapse-progression at day +100 (nonrelapse mortality only). Other secondary objectives included time to neutrophil and platelet engraftment as well as estimation of radiation doses to the whole body and organs through serial imaging studies.

Correlative studies

Expression of CD25 primary tumor cells was performed by immunohistochemistry, as previously described,22 on pre-AHCT tumor samples.

Statistical methods/trial design

This phase 1 trial followed a modified, more conservative version of the rolling 6 design of Skolnik et al.35 For a given test dose level, the schema was as follows: at most, 3 patients were under observation for DLT at any time. Patients not evaluable for DLT were replaced. When a patient evaluable for toxicity passed without a DLT, an additional patient could be accrued, up to a maximum of 6 patients. Once 3 patients were evaluated with none experiencing a DLT, up to 3 additional patients could be treated at that dose level, or the dose could be escalated. There was no intrapatient dose escalation.

Although this design does not require that 6 patients be treated per dose level, no more than 6 evaluable patients were accrued to any dose level during this dose-finding study.

All patients provided signed informed consent for participation in the clinical trial. The study was approved by the City of Hope Institutional Review Board and conducted in accordance with the principles of the Declaration of Helsinki.

Results

Patient characteristics

A total of 23 patients were consented for the protocol. Of the 23 patients, 22 were eligible for treatment between July 2015 and June 2020, but 2 did not receive treatment (Figure 1). Twenty patients received cold basiliximab, an imaging dose of 111In-basiliximab-DOTA, a therapeutic dose of 90Y-basiliximab-DOTA, and BEAM AHCT. Patient baseline characteristics are shown in Table 1. The median age was 51 years (range, 18-76). The median number of prior therapies was 1 (range, 1-4). Induction therapy consisted of cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), vincristine (Oncovin), and prednisone (CHOP; 6 patients), Cytoxan, Adriamycin, vincristine, etoposide, and prednisone (CHOEP; 8 patients); dose-escalated infusional etoposide, Adriamycin, vincristine, Cytoxan, and prednisone (DA-EPOCH; 4 patients), brentuximab, Cytoxan, Adriamycin, and prednisone (BV + CHP; 1 patient), or other (1 patient). Eighteen (90%) patients were in CR1, and 2 (10%) were in CR2. All patients had chemotherapy-sensitive disease. Salvage regimens consisted of brentuximab vedotin (3 patients) and gemcitabine-based therapy (1 patient). At the time of stem cell transplant, all patients were eligible to receive AHCT as per National Comprehensive Cancer Network guidelines.2Table 1. Baseline characteristics of patients who received RIT and BEAM based Stem Cell Transplant

Characteristic	N (%) or median (range)	
Sex		
 Female	7 (35)	
 Male	13 (65)	
Age (y) at initial treatment	51 (18-76)	
Ethnicity		
 Hispanic	5 (25)	
 White	4	
 Asian/Pacific Islander	1	
 Non-Hispanic	15 (75)	
Race/ethnicity		
 White	12 (60)	
 Asian	2 (10)	
 Black	5 (25)	
 Multiple race (Asian/Pacific Islander)	1 (5)	
Diagnosis		
 PTCL-NOS	10 (50)	
 Angioimmunoblastic T-cell lymphoma	3 (15)	
 ALK-ve ALCL	5 (25)	
 Intestinal T-cell lymphoma	2 (10)	
Stage at diagnosis		
 I	2 (10)	
 II	3 (15)	
 III	4 (20)	
 IV	11 (55)	
Disease status before the study treatment		
 CR1	18 (90)	
 CR2	2 (10)	
Chemosensitivity before the study treatment		
 Resistant	0 (0)	
 Sensitive	20 (100)	
Performance status at transplant		
 90	10 (50)	
 100	10 (50)	
Number of prior therapies	1 (1-4)	
Prior radiation therapy		
 No	19 (95)	
 Yes	1 (5)	
Prior treatments		
 CHOP	5	
 CHOEP	8	
 EPOCH	3	
 A + CHP	1	
 ABVD	1	
 Newcastle regimen	1	
 Other	1	
Salvage treatments		
 Brentuximab vedotin	3	
 Gemcitabine based	1	
ABVD, Adriamycin, Bleomycin, vinblastin, Dacarbazine; ALK-ve, Peripheral T cell lymphoma; CHOP, Cytoxan adriamycin, vincristine prednisone; CHOEP, Cytoxan, Etoposide adriamycin, vincristine prednisone; EPOCH, etoposide Cytoxan, Etoposide adriamycin, vincristine prednisone; A+CHP, Brentuximab vedotin + cytoxan adriamycin, prednisone; NOS, not otherwise specified.

Of 20 patients who received a therapeutic dose of 90Y-basiliximab-DOTA, 4 were treated with 0.4 mCi/kg, 4 with 0.5 mCi/kg, and 12 with 0.6 mCi/kg. At the end of the observation period, 14 patients were alive, and 12 remained progression free (Table 2).Table 2. Patient summary

UPN	Dose level (mCi/kg)	Age at AHCT, y	Prior lines	Diagnosis	Prior therapies	Disease status at AHCT	Response after AHCT, day 100	Current status	
1	0.4	50	1	PTCL-NOS	R-EPOCH ×6	CR1	CR	Alive without relapse ∼2 y after AHCT	
2	0.4	45	1	PTCL-NOS	R-EPOCH ×6	CR1	CR	Relapsed at day +301, died of PTCL ∼17 mos after AHCT	
4	0.4	50	1	AITL	CHOEP ×6	CR1	CR	Alive without relapse ∼1.5 y after AHCT	
5	0.4	71	1	PTCL-NOS	CHOP ×6	CR1	CR	Alive without relapse ∼2 y after AHCT	
6	0.5	48	1	HSTCL	EPOCH + BV ×6	CR1	CR	Alive without relapse ∼2 y after AHCT	
7	0.5	74	1	MEITL	CHOEP ×6	CR1	CR	Alive without relapse ∼2 y after AHCT	
9	0.5	76	1	PTCL-NOS	CHOEP ×6	CR1	CR	Relapsed at day +218, died of PTCL ∼11 mos after AHCT	
10	0.5	18	1	PTCL-NOS	CHOEP ×6	CR1	CR	Alive without relapse ∼2 y after AHCT	
11	0.6	41	2	PTCL-NOS	CHOP ×6	CR1	CR	Relapsed at day +514, still alive ∼2 y after AHCT	
12	0.6	51	1	ALK-ve ALCL	CHOEP ×6	CR1	CR	Alive without relapse ∼1 y after AHCT	
13	0.6	60	1	AITL	CHOEP ×6	CR1	Relapse	Relapsed at day +108, died of PTCL ∼21 mos after AHCT	
14	0.6	52	1	ALK-ve ALCL	CHOP ×6	CR1	CR	Alive without relapse ∼2 y after AHCT	
15	0.6	44	2	ALK-ve ALCL	ABVD – BV ×6 (CR1)	CR2	Relapse	Relapsed at day +105, died of PTCL ∼9 mos after AHCT	
16	0.6	76	2	MEITL	Newcastle regimen (CR1) Gem/Ox – CR2	CR2	Relapse	Relapsed at day +118, died of PTCL ∼18 mos after AHCT	
17	0.6	54	1	AITL	CHOEP ×6	CR1	CR	Alive without relapse ∼2 y after AHCT	
18	0.6	62	1	PTCL-NOS	CHOP ×6	CR1	CR	Relapsed at day +269, died of multiorgan failure ∼9 mos after AHCT	
19	0.6	62	1	PTCL-NOS	CHOP ×6	CR1	CR	Relapsed at day +360, still alive ∼2 y after AHCT	
20	0.6	63	4	PTCL-NOS CD30+	Cytoxan ×1, etoposide ×1, romidepsin ×3 infusions, BV ×6 – CR1	CR1	CR	Alive without relapse ∼1.5 y after AHCT	
21	0.6	46	2	ALK-ve ALCL	CHOEP ×3 – BV ×8 – CR1	CR1	CR	Alive without relapse ∼1.5 y after AHCT	
22	0.6	32	1	ALK-ve ALCL	A + CHP ×6	CR1	CR	Alive without relapse ∼7 mos after AHCT	
Alk-ve ALCL, Anaplastic large cell lymphoma; Gem/Ox, gemcitabine and oxaliplatin; HSTCL, hepatosplenic T-cell lymphoma; MEITL, monomorphic epithelial intestinal T-cell lymphoma; UPN- unidentified patient number.

Safety and tolerability

A radioactivity dose of 0.6 mCi/kg was determined to be acceptably safe and tolerable for phase 2 studies of 90Y-aTac-BEAM AHCT in PTCL. No DLTs were observed at any dose level, and the incidence of adverse event (AEs) was roughly the same among the 3 dose levels (Table 3).Table 3. AEs per Bearman scale

Organ	Grade	
DL1: 0.4 mCi/kg (n = 4)	DL2: 0.5 mCi/kg (n = 4)	DL3: 0.6 mCi/kg (n = 12)	
1	2	1	2	1	2	
Bladder	0	0	0	0	0	1	
Cardiac	0	0	0	0	0	0	
Central nervous system	0	0	0	0	0	0	
GI	0	2	2	0	5	0	
Hepatic	1	0	0	0	0	0	
Pulmonary	0	0	1	0	1	0	
Renal	0	0	0	0	2	0	
Mucositis	0	3	0	4	2	7	
DL, dose level; GI, gastrointestinal.

No patients experienced graft failure. The median time to neutrophil engraftment (absolute neutrophil count of >500) was 10.5 days (range, 10-21), and the median time to platelet engraftment (>20 × 103) was 13 days (range, 11-92; supplemental Table 1). One patient remained transfusion dependent for platelets for 15 months, and eventually her platelets recovered. At the last follow-up, she was healthy and remained in clinical remission.

Treatment-related AEs are summarized in Table 3 and supplemental Table 2 (all treatment-related AEs are reported.) According to the Bearman criteria (Table 3), the most common side effect was mucositis (experienced by 16/20 [80%] patients), mostly grade 2 that was managed as per standard guidelines and was seen at all dose levels; gastrointestinal tract (GIT) toxicity was seen in 5 of 20 (25%) patients. No grade ≥3 Bearman AEs were noted, and all AEs were managed according to standard institutional supportive measures. According to the CTCAE version 4.03 (supplemental Table 2), the most common AEs observed (all grades) were: anemia, decreased lymphocyte count, nausea, decreased platelet count, decreased neutrophil count, and decreased white blood cell count (all 100%). The most common CTCAE version 4.03 grade ≥3 AEs (supplemental Table 3) were: decreased lymphocyte count, decreased neutrophil count, decreased platelet count, decreased white blood cell count (all 100%), febrile neutropenia (85%), and anemia (55%). No cardiac toxicities or veno-occlusive disease were noted. At last follow-up, no patients had developed MDS or acute leukemia after aTac-BEAM AHCT. Aside from these events, the only other severe AEs in patients who received a therapeutic dose of 90Y-basiliximab-DOTA were a grade 3 lung infection that occurred 7 months after AHCT in 1 patient and a re-admission for grade 1 fever and grade 2 nausea on day + 28 after AHCT. There were no treatment-related deaths.

Efficacy

Survival data are shown in Figure 2. As of the end of the observation period, 6 patients (30%) had died at a median time of 17 months after AHCT (range, 9- 21). Median follow-up was 24 months (range, 9-26). Median follow-up time in surviving patients was 24 months (range, 13-26). In all patients who received a therapeutic dose of 90Y-basiliximab-DOTA, the 2-year PFS and OS were 59% (95% confidence interval [CI], 34-77) and 68% (95% CI, 42-84), respectively. Five (25%) patients died because of progressive disease, and 1 patient died because of multiorgan failure.Figure 2. Kaplan-Meier estimates of survival in all treated patients. (A) Kaplan-Meier plots of OS and PFS. (B) Tabulation of OS, PFS relapse, and nonrelapse mortality at the indicated time points after transplant.

Biodistribution, dosimetry, and pharmacokinetic studies

Twenty patients received an imaging dose of 111In-basiliximab/DOTA after cold basiliximab. Dosimetry was performed for the 17 patients who had the minimum required imaging data sets (>2 111In-basiliximab/DOTA planar scans, and at least 1 CT scan). Figure 3 shows 111In-basiliximab/DOTA SPECT and 18FDG-PET images of 1 patient (both images superimposed on coregistered CT). No patients had altered biodistribution.Figure 3. Biodistribution of 111In-basiliximab at 72 hours (left) and 18F-FDG-PET (right). There is positive uptake in right external iliac/obturator and right inguinal areas as seen on the basiliximab scan but there was no 18FDG uptake in the area.

Calculated radiation absorbed doses per unit injected activity from 90Y-basiliximab/DOTA are summarized in supplemental Table 4. Effective dose/injected activity was 5.0 ± 0.8 cGy/mCi. Organs with the highest doses/injected activity were the spleen (51 ± 21 cGy/mCi), heart (40 ± 7 cGy/mCi), and liver (25 ± 6 cGy/mCi). Red marrow received 3.1 ± 0.4 cGy/mCi. For the patients in the 0.60-mCi/kg cohort, average doses to these organs were: spleen, 24 ± 12 Gy; heart 17 ± 3 Gy; liver, 10 ± 2 Gy; and red marrow 1.2 ± 0.1 Gy. The effective dose for this cohort was 2.1 ± 0.4 Gy. Tumor doses were not measured because most patients in this HCT population had no macroscopic disease.

Basiliximab/DOTA clearance from blood plasma and serum was observed to conform to a biphasic fit. The mean and standard deviation of the half-lives of the α and β phases were 13 ± 13 hours and 153 ± 82 hours, respectively.

Correlative studies

Of 20 patients treated with 90Y-aTac-BEAM AHCT, 16 had tumor tissue evaluable for CD25 expression by immunohistochemistry (for the other 4 patients, tumor tissue was either necrotic or unavailable for evaluation.) CD25 expression in malignant T cells was found in 12 of 16 (75%) samples (supplemental Table 5). Data for number of samples with a given percentage of malignant T cells positive for CD25 were as follows: dim to moderate (not measurable), n = 4; 25%, n = 1; 30%, n = 1; 40%, n = 1; 50%, n = 2; and >80%, n = 3. One other case was mostly necrotic, with some CD25+ cells. Background tissue and tumor infiltrating lymphocytes had no or low CD25 expression. No correlation was observed between CD25 expression and either treatment response or efficacy in this limited data set.

Discussion

Our study shows that CD25–directed 90Y-basiliximab/DOTA RIT, when given in combination with standard-dose BEAM (90Y-aTac-BEAM) as conditioning for subsequent AHCT is safe in patients with PTCL requiring AHCT. The radioactivity dose was escalated from 0.4 to 0.6 mCi/kg without additional toxicity attributable to RIT, including any delays in engraftment or complications of AHCT. Based on biodistribution data, a 90Y-basiliximab/DOTA dose of 0.6 mCi/kg delivers lower radiation doses to vital organs including the heart, lungs, kidneys, liver, and spleen compared with more traditional radiation therapy, such as myeloablative TBI.36

The targeted RIT approach we evaluated has the potential to provide more robust conditioning for AHCT than do regimens currently used for patients with PTCL. Although this is a small study with varying doses of RIT and different PTCL histologies, we have observed encouraging efficacy for the 90Y-aTac-BEAM AHCT regimen. Two-year PFS and OS were 59% (95% CI, 34-77) and 68% (95% CI, 42-84), respectively, which is at least comparable with the data for chemotherapy-only conditioning regimens such as the Nordic Lymphoma Group study, which reported on 160 patients enrolled with intent to transplant; 5-year OS and PFS were 51% and 44%, respectively. The 5-year OS for patients who did not undergo transplant was 28%, clearly showing an advantage for the consolidation approach.3 Note that all our patients had achieved a state of remission before AHCT, and 90% of patients were in CR1. This is in line with the standard practice of AHCT as consolidation after initial chemotherapy. More recently, The Netherlands Cancer Registry analysis of 1427 patients showed improved outcomes with consolidative AHCT in first remission; 5-year survival of patients with ALK-ve ALCL, angioimmunoblastic T cell lymphoma (AITL), and PTCL-NOS was 81% with consolidative transplant vs 39% for those not undergoing ASCT.38 However, outcomes are far from satisfactory, with most patients relapsing within 2 years after transplant.

The use of targeted treatments in PTCL are starting to improve outcomes in specific subgroups. For patients with tumors that express CD30, the phase 3 ECHELON-2 study was the first to demonstrate the potential power of targeted therapies in the treatment of PTCL, showing that brentuximab vedotin plus CHP (A + CHP) improved PFS and OS compared with CHOP alone (5-year OS, 70 % vs 61%).39 This effect was most pronounced in patients with ALCL in which CD30 is uniformly expressed in the tumor cells. The CD30 cutoff in the study was >10%, hence other CD30-expressing histologies were also included. Subgroup analysis confirmed that the difference in outcomes was not as pronounced in non-ALCL subtypes.40 A subanalysis of this study suggested that consolidative transplant was associated with improved outcomes compared with patients who did not undergo ASCT. Median PFS was 62 months vs 32 months in patients without ALCL.41 In another study, the addition of the histone deacetylase inhibitor romidepsin to CHOP (Ro-CHOP) vs CHOP for initial therapy in PTCL failed to show a benefit over CHOP alone.42 However, a subanalysis of the study showed an improved PFS in the Ro-CHOP arm in patients with Tfh subtypes (19.5 vs 10.6 months) demonstrating an advantage of adding epigenetic therapy to conventional treatment in specific subtypes43 in which epigenetic alterations play a significant role in pathogenesis.44,45 Taken together, these studies suggest that in the treatment of PTCL, targeting specific pathways may be more effective than simply intensifying chemotherapeutic regimens.

A meta-analysis to evaluate the efficacy of AHCT as first-line consolidation for nodal PTCL has shown that this approach can improve survival. In the COMPLETE registry that prospectively collected data on the role of AHCT as consolidation in CR1 of PTCLs, the median PFS was 57.6 months.37,46 However, even after AHCT, up to 50% of patients relapse.47 We sought to improve the conditioning regimen for AHCT in PTCL by adding CD25-targeted radioimmunotherapy. External beam TBI combined with high-dose chemotherapy has been part of conditioning regimens for both autologous and allogeneic stem cell transplants. Although inclusion of TBI has enabled better disease control and reduced risk of disease recurrence, increased normal-organ toxicity and risk of secondary malignancies have limited use of TBI in conditioning regimens.48 For PTCL, there is 1 prospectively designed study from 2000 to 2006 that used TBI with high-dose cyclophosphamide as conditioning before an autologous transplant.49 These patients were either in CR or partial response at the time of transplant, and the 3-year OS rate was 48%, with a treatment-related mortality of 3.6%. These results were considered to be in line with the expected outcomes from other similar studies in B-cell lymphoma but this was the first study of this approach in PTCL.

RIT can be used to deliver radiation directly to tumor sites while simultaneously decreasing radiation dose to normal tissues, and also providing a mechanism for adding antitumor cytotoxicity to monoclonal antibody therapy, hence helping overcome the problem of myelosuppression in AHCT.50 Initial trials combining RIT with high-dose chemotherapy and stem cell rescue were conducted using anti-CD20 [131I]tositumomab (Bexxar) with high-dose etoposide and cyclophosphamide followed by stem cell rescue in relapsed B-cell lymphomas. Comparison with historical controls treated with TBI plus etoposide and cyclophosphamide showed improved PFS and OS.51 The CD20-chelator fusion molecule, [90Y]ibritumomab tiuxetan (Zevalin), was found to be safe with no added toxicity, increased risk of graft failure, or transplant-related toxicity in combination with high-dose chemotherapy for relapsed B-cell lymphoma.21,23 Importantly, the maximal dose of radiation delivered to critical organs was relatively low (25-27 cGy). Other targets for pretransplant conditioning with combined RIT and chemotherapy that have been explored include CD22 in non-HL52 and CD25 in HL.22

The results of our small phase 1 trial are encouraging and warrant further study of targeted RIT + BEAM for pre-AHCT conditioning in PTCL. No added toxicity was noted with the addition of CD25-directed RIT to BEAM. Definitive conclusions regarding efficacy are limited by the small number of patients treated, the varying histologies, and varying CD25 expression. However, 3 of 5 patients with progressive disease had no expression of CD25 on tumor cells, an observation that should be explored in a larger cohort. However, the aim of the study was to evaluate safety in the peritransplant period. A sufficiently large patient sample given the recommended 0.6 mCi/kg dose combined with sufficiently long follow-up would enable the efficacy (measured in terms of PFS and OS) of 90Y-aTac-BEAM AHCT to be compared with that of BEAM-based AHCT. A larger patient sample would also improve evaluation of the expected correlation between CD25 expression in tumor and response to 90Y-aTac RIT. Long-term toxicity and secondary malignancies should be evaluated well beyond the 24-month follow-up interval of this study. All patients in this study were in CR at time of enrollment, with little or no macroscopic residual disease as judged by FDG-PET/CT. We did not include any patients with residual disease because it is not congruent with our clinical practice to offer AHCT to these patients.

This study included various PTCL histologies representative of those seen in standard clinical practice. Future studies may be designed to identify specific histologies for which targeted RIT is especially beneficial and to better evaluate the role of CD25 positivity in relation to response. Patient selection for 90Y-aTac-BEAM AHCT might be improved by adding a means for detecting minimal residual disease in the peripheral blood. Other potential targets for RIT in PTCL include CD30, CD70, and CCR4.53, 54, 55 To obtain higher tumor cell kill, basiliximab/DOTA could be labeled with an α-emitting radionuclide such as 225actinium.

Conflict-of-interest disclosure: J.Z. is a consultant for Kyowa Kirin, Seattle Genetics, Verastem, Daiichi Sankyo, and Mundi Pharma; serves of the speakers bureau of Seattle Genetics, SecureBio, Daiichi Sankyo, and AbbVie; and reports research support from Seattle Genetics, SecureBio, Daiichi Sankyo, and AbbVie. J.W. reports grant support from RefleXion Inc, Varian Inc, Accuray Inc, Telix Inc, and Blue Earth Diagnostics, Inc. A.F.H. reports research funding from Bristol Myers Squibb, Merck, Genentech, Inc, F. Hoffmann-La Roche Ltd, Gilead Sciences, Seattle Genetics, AstraZeneca, and ADC Therapeutics; and reports consultancy with Bristol Myers Squibb, Merck, Genentech, Inc, F. Hoffmann-La Roche Ltd, Kite Pharma/Gilead, Seattle Genetics, Karyopharm, Takeda, Tubulis, and AstraZeneca. S.D. reports research funding from Bayer. A.M.W. reports consultancy and board membership with ImaginAb; and reports consultancy with AstraZeneca, and Novartis Institute for Biomedical Research. The remaining authors declare no competing financial interests.

Supplementary Material

Supplemental Tables and Figure

Acknowledgment

This research was supported, in part, by the 10.13039/100000002 National Institutes of Health (grant P30CA033572 ; City of Hope National Medical Center).

Authorship

Contribution: J.Z., J.P., and D.C. provided conceptualization and design; E.P.S., J.P., N.-C.T., J.S., J.Y.S., V.A., D.Y., E.K.P., S.D., A.S., R.N., J.Z., A.F.H., N.A.K., and A.P.N. collected and assembled data; P.Y., E.K.P., V.E.B.-A., D.C., and J.E.S. contributed vital new reagents; V.A., N.-C.T., J.P., J.Y.S., J.W., J.Z., A.M.W., D.L.S., J.R.B., and S.J.F provided data analysis and manuscript revision; and J.Z. wrote the first draft of the manuscript.

Data sets and protocols are available on reasonable request to the corresponding author, Jasmine Zain (jazain@coh.org).

The full-text version of this article contains a data supplement.
==== Refs
References

1 Kharfan-Dabaja MA Kumar A Ayala E Clinical practice recommendations on indication and timing of hematopoietic cell transplantation in mature T cell and NK/T cell lymphomas: an international collaborative effort on behalf of the guidelines committee of the American Society for Blood and Marrow Transplantation Biol Blood Marrow Transplant 23 11 2017 1826 1838 28797780
2 Horwitz SM Ansell S Ai WZ T-cell lymphomas, version 2.2022, NCCN clinical practice guidelines in oncology J Natl Compr Canc Netw 20 3 2022 285 308 35276674
3 d'Amore F Relander T Lauritzsen GF Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01 J Clin Oncol 30 25 2012 3093 3099 22851556
4 Casulo C Horwitz S Should eligible patients with T-cell lymphoma receive high-dose therapy and autologous stem cell transplant in the upfront setting? Curr Oncol Rep 12 6 2010 374 382 20737300
5 Cheng Kiat Ng L Shwei Wen Tham C Wei Inng Lim F Hematopoietic stem cell transplant in aggressive T and NK/T cell lymphoma - role of upfront autologous transplant in nodal peripheral T-cell lymphoma Blood Cell Ther 4 4 2021 92 100 36714065
6 Jethwa KD Bishton MJ Fox CP The role of high-dose chemotherapy and autologous stem cell transplant for treatment-naive patients with peripheral T-cell lymphoma: a systematic review of the literature Br J Haematol 178 3 2017 476 479 27146257
7 Zain J Transplantation Querfeld C Zain J Rosen ST T-Cell and NK-Cell Lymphomas: From Biology to Novel Therapies 2019 Springer International Publishing 269 287
8 Chen AI McMillan A Negrin RS Horning SJ Laport GG Long-term results of autologous hematopoietic cell transplantation for peripheral T cell lymphoma: the Stanford experience Biol Blood Marrow Transplant 14 7 2008 741 747 18541192
9 Hamadani M Ngoya M Sureda A Outcome of allogeneic transplantation for mature T-cell lymphomas: impact of donor source and disease characteristics Blood Adv 6 3 2022 920 930 34861680
10 Olivieri J Mosna F Pelosini M A comparison of the conditioning regimens BEAM and FEAM for autologous hematopoietic stem cell transplantation in lymphoma: an observational study on 1038 patients from Fondazione Italiana Linfomi Biol Blood Marrow Transplant 24 9 2018 1814 1822 29857196
11 Ma H O'Connor OA Marchi E New directions in treating peripheral T-cell lymphomas (PTCL): leveraging epigenetic modifiers alone and in combination Expert Rev Hematol 12 3 2019 137 146 30782038
12 Strauchen JA Breakstone BA IL-2 receptor expression in human lymphoid lesions. Immunohistochemical study of 166 cases Am J Pathol 126 3 1987 506 512 3103454
13 Waldmann TA The IL-2/IL-2 receptor system: a target for rational immune intervention Immunol Today 14 6 1993 264 270 8397768
14 Peng Y Tao Y Zhang Y Wang J Yang J Wang Y CD25: A potential tumor therapeutic target Int J Cancer 152 7 2023 1290 1303 36082452
15 Kawai H Ando K Maruyama D Phase II study of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma Cancer Sci 112 6 2021 2426 2435 33792128
16 Olsen E Duvic M Frankel A Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma J Clin Oncol 19 2 2001 376 388 11208829
17 Prince HM Duvic M Martin A Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma J Clin Oncol 28 11 2010 1870 1877 20212249
18 Berkowitz JL Janik JE Stewart DM Safety, efficacy, and pharmacokinetics/pharmacodynamics of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma Clin Immunol 155 2 2014 176 187 25267440
19 Foss FM Kim YH Prince HMM Efficacy and safety of E7777 (improved purity Denileukin diftitox [ONTAK]) in patients with relapsed or refractory cutaneous T-cell lymphoma: results from pivotal study 302 Blood 140 suppl 1 2022 1491 1492
20 Collins GP Horwitz SM Davies A Adct-301 (Camidanlumab Tesirine), a Novel Pyrrolobenzodiazepine-Based CD25-Targeting Antibody Drug Conjugate, in a Phase 1 Study of Relapsed/Refractory Non-Hodgkin Lymphoma Shows Activity in T-Cell Lymphoma Blood 132 suppl 1 2018 1658
21 Gopal AK Rajendran JG Gooley TA High-dose [131I]tositumomab (anti-CD20) radioimmunotherapy and autologous hematopoietic stem-cell transplantation for adults > or = 60 years old with relapsed or refractory B-cell lymphoma J Clin Oncol 25 11 2007 1396 1402 17312330
22 Herrera AF Palmer J Adhikarla V Anti-CD25 radioimmunotherapy with BEAM autologous hematopoietic cell transplantation conditioning in Hodgkin lymphoma Blood Adv 5 23 2021 5300 5311 34638132
23 Nademanee A Forman S Molina A A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma Blood 106 8 2005 2896 2902 16002426
24 Press OW Eary JF Gooley T A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas Blood 96 9 2000 2934 2942 11049969
25 Dancey G Violet J Malaroda A A phase I clinical trial of CHT-25 a 131I-labeled chimeric anti-CD25 antibody showing efficacy in patients with refractory lymphoma Clin Cancer Res 15 24 2009 7701 7710 20008855
26 Waldmann TA White JD Carrasquillo JA Radioimmunotherapy of interleukin-2R alpha-expressing adult T-cell leukemia with Yttrium-90-labeled anti-Tac Blood 86 11 1995 4063 4075 7492762
27 Conlon KC Sportes C Brechbiel MW (90)Y-daclizumab (Anti-CD25), high-dose carmustine, etoposide, cytarabine, and melphalan chemotherapy and autologous hematopoietic stem cell transplant yielded sustained complete remissions in 4 patients with recurrent Hodgkin's lymphoma Cancer Biother Radiopharm 35 4 2020 249 261 32275165
28 Janik JE Morris JC O'Mahony D 90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin's lymphoma Proc Natl Acad Sci U S A 112 42 2015 13045 13050 26438866
29 Krishnan A Palmer JM Tsai NC Matched-cohort analysis of autologous hematopoietic cell transplantation with radioimmunotherapy versus total body irradiation-based conditioning for poor-risk diffuse large cell lymphoma Biol Blood Marrow Transplant 18 3 2012 441 450 21801706
30 Thomas O Mahe M Campion L Long-term complications of total body irradiation in adults Int J Radiat Oncol Biol Phys 49 1 2001 125 131 11163505
31 Campo E Swerdlow SH Harris NL Pileri S Stein H Jaffe ES The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications Blood 117 19 2011 5019 5032 21300984
32 Siegel JA Thomas SR Stubbs JB MIRD pamphlet no. 16: techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates J Nucl Med 40 2 1999 37S 61S 10025848
33 Stabin MG OLINDA/EXM 2-the next-generation personal computer software for internal dose assessment in nuclear medicine Health Phys 124 5 2023 397 406 36780284
34 Cheson BD Pfistner B Juweid ME Revised response criteria for malignant lymphoma J Clin Oncol 25 5 2007 579 586 17242396
35 Skolnik JM Barrett JS Jayaraman B Patel D Adamson PC Shortening the timeline of pediatric phase I trials: the rolling six design J Clin Oncol 26 2 2008 190 195 18182661
36 Dillman RO Radioimmunotherapy of B-cell lymphoma with radiolabelled anti-CD20 monoclonal antibodies Clin Exp Med 6 1 2006 1 12 16550338
37 Lansigan F Horwitz SM Pinter-Brown LC Outcomes for relapsed and refractory peripheral T-cell lymphoma patients after front-line therapy from the COMPLETE registry Acta Haematol 143 1 2020 40 50 31315113
38 Brink M Meeuwes FO van der Poel MWM Impact of etoposide and ASCT on survival among patients aged <65 years with stage II to IV PTCL: a population-based cohort study Blood 140 9 2022 1009 1019 35544601
39 Horwitz S O'Connor OA Pro B The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma Ann Oncol 33 3 2022 288 298 34921960
40 Horwitz SM Savage KJ Illidge T The Echelon-2 trial: 5-year exploratory subgroup analyses of a randomized, double-blind, phase 3 study of brentuximab vedotin and CHP (A+CHP) vs CHOP in frontline treatment of Pts with CD30-positive peripheral T-cell lymphoma Blood 138 suppl 1 2021 135
41 Savage KJ Horwitz SM Advani R Role of stem cell transplant in CD30+ PTCL following frontline brentuximab vedotin plus CHP or CHOP in ECHELON-2 Blood Adv 6 19 2022 5550 5555 35470385
42 Bachy E Camus V Thieblemont C Romidepsin plus CHOP versus CHOP in patients with previously untreated peripheral T-cell lymphoma: results of the Ro-CHOP phase III study (conducted by LYSA) J Clin Oncol 40 3 2022 242 251 34843406
43 Camus V Thieblemont C Gaulard P Romidepsin plus cyclophosphamide, doxorubicin, vincristine, and prednisone versus cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with previously untreated peripheral T-cell lymphoma: final analysis of the Ro-CHOP trial J Clin Oncol 42 14 2024 1612 1618 38364196
44 Yamagishi M The role of epigenetics in T-cell lymphoma Int J Hematol 116 6 2022 828 836 36239901
45 Zhang P Zhang M Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma Clin Epigenetics 12 1 2020 169 33160401
46 Park SI Horwitz SM Foss FM The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: report from COMPLETE, a prospective, multicenter cohort study 125 9 2019 1507 1517
47 Vose JM Outcomes for PTCL: which pathway to success? Blood 137 19 2021 2570 2571 33983423
48 Han C Liu A Wong JYC Estimation of radiation-induced, organ-specific, secondary solid-tumor occurrence rates with total body irradiation and total marrow irradiation treatments Pract Radiat Oncol 10 5 2020 e406 e414 32302694
49 Reimer P Rudiger T Geissinger E Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study J Clin Oncol 27 1 2009 106 113 19029417
50 Badger CC Krohn KA Shulman H Flournoy N Bernstein ID Experimental radioimmunotherapy of murine lymphoma with 131I-labeled anti-T-cell antibodies Cancer Res 46 12 Pt 1 1986 6223 6228 3779642
51 Press OW Emerging immunotherapies for non-Hodgkin lymphomas: the tortoise approaches the finish line Ann Intern Med 132 11 2000 916 918 10836921
52 Laszlo GS Sandmaier BM Kehret AR [211At]astatine-based anti-CD22 radioimmunotherapy for B-cell malignancies Leuk Lymphoma 64 7 2023 1335 1339 37170642
53 Marques-Piubelli ML Solis Soto L Iyer SP CD70 expression in mature T-cell lymphomas Blood 138 suppl 1 2021 4493
54 Sabattini E Pizzi M Tabanelli V CD30 expression in peripheral T-cell lymphomas Haematologica 98 8 2013 E81 E82 23716537
55 Tobinai K Takahashi T Akinaga S Targeting chemokine receptor CCR4 in adult T-cell leukemia-lymphoma and other T-cell lymphomas Curr Hematol Malig Rep 7 3 2012 235 240 22538464
