Pralatrexate injection combined with CHOP for treatment of PTCL: results from the Fol-CHOP dose-finding phase 1 trial

Peripheral T-cell lymphoma (PTCL) refers to a heterogeneous group of aggressive mature T-cell non-Hodgkin lymphomas accounting for 10% to 15% of all newly diagnosed non-Hodgkin lymphomas.^1,2 Of 28 distinct clinical entities, the most common subtypes of PTCL, representing two-thirds of all PTCL cases in North America, include PTCL not otherwise specified (PTCL NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL). The median overall survival (OS) of PTCL is low (<2 years), with a reported 5-year survival for the most common subtypes being <50%.^2-5 

Firstline, standard of care (SOC) treatment of PTCL often comprises combination therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Despite its widespread use, CHOP has not been studied in prospective, randomized studies and was associated with a dismal 5-year OS of only 37% in a retrospective meta-analysis of 2912 patients with PTCL treated with CHOP or CHOP-like regimens.^6-8 However, no other single-agent or combination regimen has demonstrated superior efficacy to CHOP with the exception of brentuximab vedotin (BV) + cyclophosphamide, doxorubicin, and prednisone (CHP) for CD30⁺ PTCL, and it, therefore, remains a primary choice for firstline therapy for non-ALCL PTCL. Various strategies to modify the CHOP regimen have been investigated in an effort to increase response rates and improve durability of responses, without any clear improvements to long-term efficacy being observed. Strategies have included the addition of other agents, including biologics (“CHOP + X”), more intensive dosing administration, and, for patients who reach complete remissions, high-dose chemotherapy using autologous stem cell rescue as consolidation therapy.^9-11 Allogeneic stem cell transplantation is also recognized as a feasible option for patients with PTCL who are candidates for the procedure, although significant treatment-related toxicity has been observed.^12-14 Although the reported survival outcomes remain quite poor, response rates for CHOP-based therapies have been relatively high. As an example, a recent trial comparing CHOP vs BV-CHP in CD30⁺ PTCLs showed an overall response rate (ORR) of 72% for CHOP and complete response (CR) of 56%.¹⁵ Overall, the available data related to PTCL treatment shows that firstline CHOP can provide an initial response for many patients; however, fewer are able to achieve CR, and even less achieve durable remissions.

Pralatrexate monotherapy has demonstrated activity in PTCL and was the first drug approved in the United States by the US Food and Drug Administration for treatment of relapsed/refractory (R/R) PTCL in 2009, based on doses of 30 mg/m² weekly for 6 weeks of a 7-week treatment cycle and an ORR of 29% in a heavily pretreated population.^13,16 In 2016, O’Connor et al presented the findings of their case match control analysis of 83 patients with R/R PTCL treated in the PROPEL study, compared with matched controls.¹⁷ Despite the heavily treated PROPEL population, the median OS of pralatrexate-treated patients was significantly higher at 16.6 months than of matched controls at 4.0 months (hazard ratio, 0.426).¹⁷ Further evidence for its activity in PTCL was provided by the phase 3 LUMIERE trial, which randomized patients to the investigative drug alisertib and SOC comparator (investigator choice of gemcitabine, romidepsin, or pralatrexate); pralatrexate was administered to 80 participants (60% of 3 possible controls) and resulted in a CR rate of 25%, highest of the drugs studied in the trial (CR for investigative drug, 18%; CR for another SOC comparator, 6%).¹⁸ 

This single-agent activity provided the rationale for adding pralatrexate to CHOP in the frontline setting. Pralatrexate and each of the components of the CHOP regimen target different aspects of tumor cell growth and proliferation through different mechanisms of action. This suggests the potential that a new combination regimen may provide for synergistic antitumor effect and have limited additive toxicities.

Herein, we describe the results of a phase 1 dose-escalating study investigating the maximum tolerated dose (MTD) of pralatrexate in combination with CHOP regimen and associated response rates in patients with newly diagnosed PTCL.

This multicenter, open-label, dose-finding, dose-escalation phase 1 trial was conducted in 2 parts: the first with the primary objective to evaluate the MTD of pralatrexate in combination with CHOP and the second part with an expansion cohort of 30 patients treated at the MTD to better characterize safety and efficacy of 6 cycles of the pralatrexate-CHOP (Folotyn-CHOP [Fol-CHOP]) combination.

The study was reviewed and approved by the institutional review boards at each of the 4 participating sites and was registered at as NCT02594267. The study conduct complied with the Declaration of Helsinki and followed International Conference on Harmonization Guidelines for Good Clinical Practice. All participating patients provided written informed consent and understood that study participation was voluntary.

Patients were eligible if they were aged ≥18 years with a newly diagnosed, untreated, histologically confirmed diagnosis of PTCL of any stage (I-IV) based on local pathology review and were eligible for CHOP chemotherapy. PTCL subtypes were classified based on the 2016 World Health Organization classification and included ALCL, ALK-positive status; ALCL, ALK-negative status; ATCL; enteropathy-associated T-cell lymphoma; extranodal natural killer/T-cell lymphoma, nasal type; hepatosplenic T-cell lymphoma; PTCL NOS; and subcutaneous panniculitis-like T-cell lymphoma.¹⁹ Pathological diagnoses were made by each participating facility. Patients were required to have adequate cardiac function and acceptable hematologic, hepatic, and renal functions, as defined by an absolute neutrophil count ≥ 1.5 × 10⁹/L, platelet count ≥ 100 × 10⁹/L, bilirubin level ≤ 1.5 mg/dL, aspartate aminotransferase and alanine aminotransferase levels ≤ 2.5 upper limit of normal, and creatinine level ≤ 1.5 mg/dL or calculated creatinine clearance ≥ 50 mL per minute. Patients also had to have an Eastern Cooperative Oncology Group performance status ≤ 2. Exclusion criteria included current concurrent malignancy (except nonmelanoma skin cancer or carcinoma in situ of the cervix) or life-threatening disease. Those with a history of prior malignancies or life-threatening conditions should have been disease free for ≥5 years. Patients were also excluded if they had congestive heart failure, uncontrolled hypertension, central nervous system metastases, uncontrolled intercurrent illness, or therapy with any investigational therapies within 30 days of study treatment.

In part 1 of this study, patients were enrolled in a traditional 3 + 3 dose-escalation scheme, starting with dose level 1, with dose escalation as shown in supplemental Table 1. Pralatrexate was administered at 10, 15, 20, 25, or 30 mg/m² as an IV on days 1 and 8 of a standard 21-day CHOP regimen (cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and vincristine 1.4 mg/m² [maximum, 2 mg] on day 1 and oral prednisone 100 mg on days 1-5).

A DLT was defined as an adverse event (AE) that, because of its type, severity, or relationship to study drug, must be counted toward determining the MTD. For purposes of determining the MTD of pralatrexate (Folotyn; Acrotech Biopharma, East Windsor, NJ) plus CHOP (Fol-CHOP) treatment, AEs that were considered DLTs when they occurred during the first treatment cycle included severe infections (grade 4); grade 4 neutropenia lasting for ≥7 days despite granulocyte colony-stimulating factor administration; any grade 4 thrombocytopenia or any grade thrombocytopenia with clinically significant bleeding (excluding epistaxis); or grade ≥3 study treatment-related nonhematologic toxicity, excluding nausea/vomiting in the absence of appropriate antiemetic therapy that occurred during the first cycle of the Fol-CHOP therapy.

Once the MTD was established in part 1, an expansion cohort (part 2) applying the MTD was included to allow for better characterization of efficacy and safety. (Figure 1) Patients were treated with the pralatrexate MTD on days 1 and 8 of each 21-day cycle, administered ∼15 minutes after CHOP. Treatment was repeated every 21 days (1 cycle) for up to 6 cycles.

Patients received prophylaxis with acyclovir and sulfamethoxazole/trimethoprim during the study as well as primary prophylaxis with growth factors (filgrastim or pegfilgrastim) starting in cycle 1 (after the second dose of pralatrexate). All patients were recommended with initiate vitamin supplementation with folic acid and vitamin B12, per the currently approved label. Folic acid (1.0 mg by mouth daily) was initiated at least 10 days before pralatrexate administration. Vitamin B12 (1 mg IM) was administered within 10 weeks before the initiation of pralatrexate and was allowed to be administered during screening. Subsequent vitamin B12 injections were administered the same day as treatment with pralatrexate, and patients received vitamin B12 every 8 to 10 weeks during treatment with pralatrexate.

Patients were instructed to take leucovorin tablets (25 mg) 3 times a day for 2 days beginning 24 hours after each pralatrexate treatment as mucositis prophylaxis.²⁰ The next dose of pralatrexate began at least 72 hours after the last dose of leucovorin administration.

Patients participated in the study for ∼26 weeks, which included a screening period (up to 30 days), up to six 3-week treatment cycles (18 weeks), and an end-of-study visit, which occurred at least 30 days after the last dose of pralatrexate.

All patients who received ≥1 dose of pralatrexate were evaluable for safety, which was assessed by reported AEs, laboratory assessments, and physical examinations, and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events scale, version 4.03. AEs were characterized by intensity (severity), causality, and seriousness by the investigator and recorded from the first dose of pralatrexate until at least 30 days after the last dose.

Pharmacokinetic (PK) studies were performed during the part 2 of the study and included collection of blood samples for PK analysis of pralatrexate for the first 12 patients at before injection, end of injection, and 0.5, 1, 3, 6, 10, 16, and 24 hours after the end of pralatrexate injection during cycle 1, dose 1.

Pralatrexate comprised a mixture of R- and S-diastereomeric folate derivatives and, as folate, has an important role in cell growth and proliferation.²¹ The characterization of the plasma concentrations of pralatrexate (S-Diastereomer [PDX-10a] and R-Diastereomer [PDX-10b]) was a key secondary objective, determined using a validated LC-MS/MS bioanalytical method. PK parameters of pralatrexate (PDX-10a and PDX-10b) were calculated based on respective drug concentration–time data by a noncompartmental method using Phoenix WinNonlin (Certara, Princeton, NJ) version 8.3.1 or higher. The following PK parameters of pralatrexate (PDX-10a and PDX-10b) were estimated: area under the curve, rate of absorption, T_max, total clearance, T_1/2, and volume of distribution.

Disease response was determined by investigators at each participating facility using protocol-specified integrated response criteria (Cheson classification, per the International Working Group Criteria).²² Response evaluation recorded and reported every 2 cycles during the course of 6 cycles of Fol-CHOP (end of cycles 2, 4, and 6 and at 6, 9, and 12 months [end-of-study visit]).

The ORR was estimated by a combination of CR + partial response (PR) based on tumor scan at the end of treatment after 6 cycles of Fol-CHOP. Tumor scan performed in this study included both computed tomography and positron emission tomography–computed tomography.

The primary objectives of the study were to evaluate the MTD of pralatrexate in combination with CHOP (Fol-CHOP) for newly diagnosed patients with PTCL in part 1 of the study and evaluate the ORR after 6 cycles of Fol-CHOP in part 2. Key secondary objectives included the evaluation of progression-free survival (PFS) and safety and tolerability of Fol-CHOP as well as the characterization of PK of pralatrexate in combination with CHOP.

This study was planned to enroll 50 patients, which included a maximum of 6 patients in each cohort in part 1 until the MTD was identified and not determined by statistical power considerations. The decision to include up to 6 patients at each dose level cohort was based on the following considerations: if 1 DLT is observed among 6 patients, the estimated DLT rate is 16.7%, with a 90% confidence interval of 0.9% to 58.2%; and if 2 DLTs are observed among 6 patients, the estimated DLT rate is 33.3%, with a 90% confidence interval of 6.3% to 72.9%.

After the MTD had been identified, an additional 30 patients were planned to be treated to confirm the tolerability and assess efficacy in part 2. Estimated response rates were calculated along with corresponding 95% binomial confidence intervals.

Additional patients could be enrolled to replace unevaluable patients in cases of discontinuations unrelated to treatment-emergent AEs (TEAEs). Appropriate descriptive statistics were performed. Statistical analyses were performed using SAS version 9.4.

The extent of the patients’ exposure to pralatrexate and CHOP were assessed based on 2 variables, cumulative dose received and relative dose intensity. The incidence of DLTs as well as AEs were tabulated by dose level. AEs were summarized based on the type as well as maximum grade and duration across patients for each dose level, as well as in the part 2 MTD expansion.

The populations presented for analysis included the safety analysis population, which consisted of all patients who signed informed consent, enrolled, and received at least 1 dose of the study drug, and the efficacy was assessed in the evaluable population, which included all patients who received at least 1 dose of pralatrexate and had at least 1 postbaseline tumor assessment.

A total of 52 patients were screened at the 4 participating institutions between 2016 and 2018. There were no screen failures; thus, 52 patients were enrolled and 34 completed the study. Patient characteristics are shown in Table 1. In part 1, there were 4 patients enrolled at dose level 10 mg/m²; 3 at dose levels 15 mg/m², 20 mg/m², and 25 mg/m² (1 each); and 6 at dose level 30 mg/m². Patient disposition is shown in Figure 2. Although the study planned to enroll 3 patients in cohort 1, because of a protocol deviation of a patient enrolled in cohort 5 receiving an incorrect dose of 10 mg/m², the dose level specified for cohort 1, the patient continued treatment and was included in the analysis of that dose level (cohort 1), and a subsequent replacement cohort 5 patient was enrolled. A summary of pralatrexate exposure, including the cumulative dose and relative dose intensity of pralatrexate, is shown in Table 2, and a summary of exposure to pralatrexate, cyclophosphamide, vincristine doxorubicin, and prednisone is shown in supplemental Table 3.

At the time of initial diagnosis using the 2016 World Health Organization criteria, the majority of patients (n = 34 [65.4%]) had PTCL NOS, 9 (17.3%) had AITL; 7 (13.5%) had ALCL, ALK-negative status; 1 (1.9%) had ALCL, ALK-positive status; and 1 (1.9%) had hepatosplenic T-cell lymphoma.

The primary end point of the study was to determine the MTD of Fol-CHOP in part 1 of the study, which was completed with 19 patients. In part 1, on days 1 and 8 of each cycle, patients were treated with 10, 15, 20, 25, and 30 mg/m² of Fol-CHOP per dose escalation, in 5 sequential cohorts. No patients experienced DLTs in cohorts 1, 2, 3, 4, and 5, and the maximum dose administered was pralatrexate 30 mg/m², which was declared the MTD and selected as the dose for part 2.

Of 52 patients enrolled (part 1 + part 2), all were treated with at least 1 dose of pralatrexate. Of the 52 patients, 50 had at least 1 postbaseline tumor assessment and were included in the efficacy analysis. The best ORR observed in 50 evaluable patients was 86% (95% CI, 73.26-94.18), which included 33 patients (66.0%) with CR and 10 (20.0%) with PR. Two patients (4.0%) had a best overall response of stable disease, and 4 (8.0%) had progressive disease. The time to median of PFS was not estimable for this population because of the small sample size. Responses according to the dose level are shown in Table 3.

Median duration of response was not estimable for all cohorts at each dose level in part 1 because not enough patients had experienced an event (progression of disease or death) at the time of data analysis cutoff (1 patient each had an event at the 10 mg/m², 15 mg/m², and 25 mg/m² dose levels, and 8 patients had an event in the expansion cohort). Overall, 11 patients (22%) experienced progressive disease in this study. Time to median of PFS was not estimable for this population because of a small sample size.

In part 2, a total of 33 patients were treated with 30 mg/m² of pralatrexate in combination with CHOP; however, only 31 were evaluable. Of the 31, the end of treatment ORR (after 6 cycles) was observed in 26 patients (83.9%), with 20 patients (64.5%) reporting CR and 6 (19.4%) reporting PR. Four patients (12.9%) had a best overall response of progressive disease. The 95% CI of overall response (CR + PR) was found to be 66.27% to 94.55%.

The response per PTCL subtype is shown in Table 4. For PTCL NOS (n = 34), the most common histology, 71% achieved CR and 18% achieved PR as their best overall response.

There were pralatrexate dose modifications noted in this study and included 11 instances of dose delay because of an AE in 9 patients (cohort 2, n = 2; cohort 3, n = 2; cohort 5, n = 2; and expansion, n = 3) and 6 instances of dose reduction in 6 patients (cohort 5, n = 1; and expansion, n = 5). Details of the reasons for delay, timing of delays, and patient characteristics are included in supplemental Table 2. Two patients in cohort 5 are included in the dose-reduction and -delay groups. Of those patients who experienced a dose reduction, the best overall response was CR for 3 and PR for 2, and 1 patient (had 1 dose delayed and 1 reduced due to AEs) had progressive disease. Of those patients who had a dose delayed, the best overall response for 6 was CR and for 2 PR, and the same patient noted earlier, experiencing dose-reduction delay, had progressive disease.

A total of 18 patients discontinued from the study before completing all per protocol dosing and/or follow-up. Of the patients who discontinued, the best overall response was CR for 6 and PR for 4, and 2 had stable disease, 4 had progression of disease, and 2 were not evaluable.

TEAEs were reported for all 52 patients, with the most frequently reported being fatigue (75.0%), constipation (57.7%), mucosal inflammation and nausea (51.9% each), anemia (42.3%), vomiting (28.8%), diarrhea (26.9%), dizziness, neutropenia, and dyspnea (25.0% each). Thirty-five patients (67.3%) experienced grade 3/4 TEAEs, the most common of which were anemia (21.2%), neutropenia (19.2%), febrile neutropenia (11.5%), fatigue, mucosal inflammation, nausea, and vomiting (7.7% each).

Forty-nine patients (94.2%) experienced TEAEs considered to be related to pralatrexate treatment, the most common of which were fatigue (51.9%), mucosal inflammation (48.1%), nausea (44.2%), constipation (40.4%), anemia (36.5%), and vomiting (25.0%).

Fifty-one patients (98.1%) experienced TEAEs considered to be related to CHOP treatment, the most common of which were fatigue (53.8%), nausea (42.3%), constipation (50.0%), anemia (36.5%), vomiting (25.0%), mucosal inflammation, and neutropenia (23.1% each).

A summary of TEAEs by severity experienced by >1 patients is included in Table 5. A table of all reported TEAEs according to the severity are detailed in supplemental Table 3.

Because of TEAEs, 9 patients were discontinued from pralatrexate treatment and 7 from CHOP. The AEs that resulted in discontinuation are detailed in Table 6. Eight patients (1 in cohort 5 and 7 in expansion) required a pralatrexate dose and/or schedule reduction due to AEs, whereas 4 patients, all in expansion, required a CHOP dose and/or schedule reduction.

Nineteen patients (36.5%) experienced a total of 35 SAEs. SAEs reported for >1 patient included febrile neutropenia 6 (11.5%), anemia 3 (5.8%), nausea, and pneumonia aspiration (3.8% each). SAEs were considered to be related to pralatrexate for 10 patients (19.2%), including 3 patients (5.8%) each with SAEs of anemia and febrile neutropenia; all other pralatrexate-related SAEs were reported for 1 patient (1.9%) each. SAEs were considered to be related to CHOP for 12 patients (23.1%), including 4 (7.7%) with febrile neutropenia, 3 (5.8%) with anemia, and 2 (3.8%) with nausea; all other CHOP-related SAEs were reported for 1 patient (1.9%) each.

Overall, 1 patient (1.9%) died during the study or within 30 days of the last dose of the study treatment. The cause of death for the patient was abdominal sepsis.

The PK parameters obtained after the cycle-1 day-1 dose of pralatrexate (PDX-10a and PDX-10b) in the plasma are presented in supplemental Table 5. The rate of absorption for PDX-10b was found to be 13.4% higher than that of PDX-10a. The extent of absorption (area under the curve) for PDX-10b was found to be 44.8% higher than that of PDX-10a. T_1/2 and T_max were found to be similar for both analytes, at ∼4.5 hours and 0.1 hour, respectively. The total clearance for PDX-10a was found to be 47% higher than that of PDX-10b. The volume of distribution for PDX-10a was found to be 52% higher than that of PDX-10b.

This was the first prospective study, to our knowledge, to evaluate the Fol-CHOP for patients with PTCL. A total of 52 patients were enrolled in the study, and 33 patients in the part 2, expansion, phase received pralatrexate at dose of 30 mg/m² in combination with CHOP every 21 days for up to 6 cycles. The primary objective of the part 1 of this study was to evaluate the MTD of pralatrexate in combination with CHOP and, for the part 2, characterize safety and efficacy of the MTD in an expansion cohort. The Fol-CHOP regimen was reasonably well tolerated and resulted in an 86% ORR and 66% CR rate. Median duration of response was not estimable because not enough patients had experienced an event (progression of disease or death) at the time of data analysis cutoff, and time to median of PFS was not estimable for this population because of the small sample size. We recognize this as a limitation of these study results; because this is a phase 1 protocol and did not stipulate long-term follow-up data collection on eCRF; however, PFS and EFS will be captured in the design of an upcoming phase 3 study.

The toxicity profile of the combination therapy was manageable; the most common grade ≥3 AEs were anemia (21.2%), neutropenia (19.2%), febrile neutropenia (11.5%), fatigue, mucosal inflammation, nausea, and vomiting (7.7% each).

CHOP has often been used as a comparator in PTCL treatment trials, with an OS at 24 months of 50% to 76%.^23-26 In efforts to improve outcomes, a number of other agents combined with CHOP have been evaluated in the past decade, including belinostat, romidepsin, and azacitidine. In the Bel-CHOP study, patients with PTCL, with a median age of 63 years, received belinostat (1000 mg/m² once daily) + standard CHOP for 6 cycles, resulting in an ORR of 86% and CR of 71%.²⁶ All patients experienced AEs, and serious events occurred in 43%, including febrile neutropenia (17%) and pyrexia (13%).²⁷ A recent phase 3 trial combining romidepsin with CHOP reported a median PFS of 12.0 months compared with 10.2 months for CHOP alone, with an ORR of 63% vs 60%, respectively.²³ Although the addition of romidepsin to CHOP did not lead to improvements in response rates or OS and increased the frequency of grade ≥ 3 TEAEs, including thrombocytopenia (50%), neutropenia (49%), anemia (47%), and leukopenia (32%), an exploratory analysis of centrally confirmed TFH lymphomas, such as AITL, did identify extended PFS in the romidepsin with CHOP arm (19.5 months) compared with CHOP alone (10.6 months).²³ Oral azacitidine has been previously studied in AITL but more recently studied in PTCL in addition to standard CHOP. A phase 2 study of 17 patients with AITL or PTCL-TFH reported CR rates of 88% for patients with AITL or PTCL-TFH, with neutropenia (71%) being the most common.²⁸ 

A recent review of 55 clinical studies that used CHOP or CHOP-like regimens as comparators for novel combinations concluded that with only 1 exception (BV + cyclophosphamide, doxorubicin, and prednisone [A + CHP], as reported in the ECHELON-2 trial), other combinations showed no statistically significant benefit over CHOP alone, in terms of OS or PFS in patients with PTCL.^15,26,29 

Comparison of outcomes in PTCL studies should be made with the recognition that there are wide variations in the characteristics of enrolled participants. Median ages that have been reported range from 33 to 74 years, whereas in this study, the median age was 62 years, gender proportions were variable, and there was a mix of PTCL subtypes. In our study, the addition of Fol-CHOP resulted in favorable OR and CR rates. Although pralatrexate led to an ORR of 29% patients with PTCL in the landmark PROPEL study, a lower response rate in patients with AITL subtype was seen. However, other studies, including retrospective analyses, found a more favorable response in AITL. An international case match control analysis of PROPEL was conducted, reporting superior OS for patients treated on PROPEL compared with historical controls from an international PTCL database that were rigorously matched against PROPEL criteria using propensity score matching algorithm. Notably, the OS estimates for AITL subtype were 5.5 months for the historical controls and 9.77 months with PROPEL.³⁰ Chihara et al reported a median OS after first, second, and third relapse for patients with AITL of 15.0, 8.3, and 6.0 months, respectively.³¹ Pralatrexate was also evaluated as an investigator-selected single-agent comparator in the Lumiere Study of alisertib in R/R PTCL, which reported an ORR of 43% for pralatrexate and 33% for alisertib.¹⁸ 

Within the PTCL trials including pralatrexate, the development of oral mucositis grade ≥2 has been reported at a rate of 52%.¹³ The use of leucovorin (d,l-folinic acid) as an adjunct to pralatrexate therapy has been studied as a strategy to mitigate mucositis in patients with PTCL and has demonstrated a significant reduction in the rates of grade ≥2 and grade ≥3 mucositis.²⁰ To our knowledge, this study was one of the first studies to investigate the prospective use of calcium leucovorin for mucositis prophylaxis. In our study, patients were instructed to take leucovorin tablets (25 mg) 3 times a day for 2 days, beginning 24 hours after each pralatrexate treatment, as prophylaxis. We reported an overall incidence of any mucositis of 51.9%: 28.8% with grade 1 severity, 15.4% with grade 2 severity, 7.7% with grade 3 severity, and no cases of grade 4 mucositis. Comparatively, in the PROPEL trial, 71% experienced any grade of mucositis, with 18% having grade 3 and 4% having grade 4 severity.¹³ 

The primary objective of this study was met; the Fol-CHOP regimen was reasonably well tolerated with an MTD of 30 mg/m² and demonstrated a promising ORR of 83.9% (20 CRs and 6 PRs) at CHOP + pralatrexate 30 mg/m², as assessed by treating investigators. The nature of this being a phase 1 trial, without long-term survival data to assess durability of responses, precludes any conclusions as to the superiority of particular regimens. The ORR was encouraging, comparable with the ORR seen in other studies of CHOP-based regimens in PTCL, and the toxicity profile was manageable, although dose adjustments for each component of Fol-CHOP were not infrequent. Other dosing strategies for Fol-CHOP may need to be explored to allow for a higher dose intensity. These findings have provided supportive evidence toward the development of an upcoming clinical trial (2024), further investigating the Fol-CHOP treatment regimen as a firstline treatment for PTCL.

The authors thank the patients who participated in this trial, their families, the investigators, and staff at all the clinical sites. The authors acknowledge April Ingram for her valuable administrative support and writing contributions.

This work was supported by Acrotech Biopharma Inc.

Contribution: All authors contributed to the concept and study design; analyzed and interpreted data, reviewed the first draft of manuscript, provided critical scientific input, gave final approval for manuscript, and were accountable for all aspects of the work.

Conflict-of-interest disclosure: S.P.I. reports consultancy fee from CRISPR, Merck, Rhizen, Seagen, Acrotech, Innate, Myeloid Therapeutics, AstraZeneca, Dren-Bio, Ono, and Trillium/Pfizer; research funding from CRISPR, Rhizen, Seagen, Acrotech, Innate, Myeloid Therapeutics, AstraZeneca, Dren-Bio, Ono, Citius, and Trillium/Pfizer; honoraria from the American Society of Hematology, American Society for Transplantation and Cellular Therapy, Seagen, Curabio, and Target Oncology; and membership on a board or advisory committee of Seagen, Acrotech, and Trillium/Pfizer. S.K.B. reports consultancy fee from Acrotech, Affimed, and Kyowa Kirin; membership on a board or advisory committee of Acrotech, Affimed, Daiichi-Sankyo, Janssen, Kyowa Kirin, and Seagen. P.B.J. declares no competing financial interests.

Correspondence: Swaminathan P. Iyer, Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, Unit 429, Houston, TX, 77030; email: spiyer@mdanderson.org.