Real-life Experience With Rituximab-CHOP Every 21 or 14 Days in Primary Mediastinal Large B-cell Lymphoma

Abstract

Background/Aim: Primary mediastinal large B-cell lymphoma (PMLBCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL), whose prognosis has greatly improved since the incorporation of the anti-CD20 monoclonal antibody rituximab into current therapeutic regimens. Evidence, however, on the optimal time interval between consecutive chemoimmunotherapy (CIT) cycles is still scarce. This study aimed to evaluate the efficacy outcomes of the more commonly administered 3-weekly regimens to the biweekly ones in a PMLBCL patients’ population, who were mostly treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP-21) or R-CHOP-14.

Patients and Methods: We retrospectively studied our cohort of consecutively treated PMLBCL patients, focusing on their treatment density, in order to determine possible differences in treatment outcomes.

Results: CIT, in the form of both R-CHOP-21 as well as R-CHOP-14 (or similar regimens), is highly active in PMLBCL, with low rates of early treatment failure. In our cohort of patients, R-CHOP-14 did not result in a meaningful improvement of freedom from progression (FFP) or overall survival (OS).

Conclusion: Both R-CHOP-14 and R-CHOP-21 are probably equally effective in PMLBCL, yet further, prospective, randomized studies are warranted to clarify whether dose-dense regimens can be associated with better disease control and long-term results.

Primary mediastinal large B-cell lymphoma (PMLBCL) is usually characterized by a rapidly progressive anterior mediastinal mass, often with local invasion and compressive manifestations, predominantly affecting younger, and more commonly female patients (1). It is a well-established clinicopathologic entity, described separately from diffuse large B-cell lymphomas (DLBCLs) in the current World Health Organization (WHO) classification, arising from putative thymic B-cells and comprising 2-3% of all non-Hodgkin lymphomas (NHLs) (2).

Similarly to DLBCL and other B-cell NHLs, the anti-CD20 monoclonal antibody rituximab has greatly improved the treatment results among PMLBCL patients, producing a statistically significant increase in disease control and overall survival (OS) (3,4). In fact, chemoimmunotherapy (CIT) with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP-21) is frequently used in the first-line management of PMLBCL patients, usually followed by consolidative radiotherapy (RT), with reported 5-year event-free/progression-free survival (EFS/PFS) and overall survival (OS) rates of 57-88% and 70-89% respectively (5). On average, the 5-year EFS/PFS and OS after R-CHOP is 75-80% and 85-90% respectively (6). Exceptional results have also been reported in a single-arm prospective phase 2 study from the National Cancer Institute (NCI) with the dose-adjusted infusional regimen consisting of etoposide, doxorubicin, cyclophosphamide with vincristine, prednisolone plus rituximab (DA-EPOCH-R), in which patients did not routinely receive consolidative RT (7), although real-life results seem somewhat inferior (8-12).

The dose-dense R-CHOP-14 regimen, i.e., R-CHOP administered every 14 days with G-CSF support, has failed to improve outcomes compared to R-CHOP-21 in the treatment of DLBCL (13-16), but may be a reasonable option in the young population of patients with PMLBCL (17). In fact, retrospective studies suggest that R-CHOP-14 may be superior to R-CHOP-21 in PMLBCL, but this has not been shown in a randomized fashion and such comparisons suffer from important limitations (18-21).

Since it is still not clear whether any of the aforementioned regimens yields significantly superior results compared to the rest (5), treatment intensification for PMLBCL patients with regimens other than R-CHOP-21 may be a less attractive alternative for at least some treating physicians. This retrospective study aimed to evaluate the efficacy outcomes of R-CHOP-21 versus (vs.) R-CHOP-14 in our cohort of PMLBCL patients, with or without consolidative RT.

Patients and Methods

Patients, staging and laboratory evaluation. We retrospectively analyzed 339 non-pediatric patients with PMLBCL, all of whom received treatment with R-CHOP-21 and R-CHOP-14 (or similar regimens) between late 2000 and 2020 in the cooperating Hellenic and Cypriot Hematology departments. The study was approved by the Laikon General Hospital Institutional Review Board (approval number 309). As described in previous publications from our group, patients were eligible for inclusion if they had presented with a clinical picture (dominated by a prominent mediastinal mass) and a histology report consistent with PMLBCL according to the REAL or WHO classifications (4,6,22-24). Our patient cohort was derived from 33 Institutions. Cases were PMLBCL patients consecutively treated with R-CHOP-based regimens during the study period. A minority of patients was treated with DA-EPOCH-R during the study period in some Centers after a change in the Institutional policy; however, only consecutive patients treated with R-CHOP in these canters prior to the adoption of DA-EPOCH-R were included in this study. Patients were clinically staged according to the Ann Arbor staging system (25,26) using standard staging procedures. In accordance with our previous reports (4,6), stage IV was assigned only if noncontiguous extensive lymphoma spread to extranodal (“E”) sites was documented. Contiguous spread within the thorax was considered stage II even in the presence of radiologically-evident chest wall, osseous, lung, pleural, or pericardial involvement. Patients with solitary lung lesions that were adjacent (proximal) but not contiguous to the mediastinal mass were also considered “E” and not stage IV (4,6), whereas patients with multiple lung lesions were assigned as stage IV. Bulky disease was defined as a mediastinal mass ≥10 cm. A proportion of patients also underwent positron emission tomography (PET) in addition to conventional staging in the more recent years, but only the results of conventional staging were taken into account (27). Hemoglobin, white blood cell counts and differential, erythrocyte sedimentation rate (ESR), serum albumin and serum lactate dehydrogenase (LDH) levels were all measured by standard assays. Anemia was defined as hemoglobin levels <13 g/dl and <11.5 g/dl in men and women respectively (28). The International Prognostic Index (IPI) score was calculated along with its age-adjusted version (aaIPI) (29) since most patients were younger than 60 years old. Exact values for IPI and aaPI were available for 313 patients, while in 325 patients an aaIPI score ≥2 was documented but its exact value could not be calculated. Finally, we also applied our recently published prognostic models, namely any extranodal involvement (stage IV or IIE/IIIE) plus LDH twice (or exceeding) the upper normal limit [LDH ≥2×ULN (Upper Limit of Normal)] (E-IV/LDH model), or any extranodal involvement plus bulky disease (E-IV/bulk model) (6).

In patients responding to CIT, RT was used at the discretion of the treating physician, but, in fact, this decision was affected by PET/CT results in the PET era (30,31). Following general PET availability, RT was given to almost all PET-positive patients, defined by the International Harmonization Project (IHP) criteria (32,33) or as Deauville 5-point scale scores (D5PSS) 3-5. On the contrary, the use of RT for patients with clearly negative PET/CT - defined as D5PSS 1 or 2 - was at the discretion of the treating physician. Generally, RT tended to be omitted during the most recent years, but this reflected the strategy of each participating center.

Statistical analysis. Freedom from progression (FFP) was defined as the time interval between treatment initiation and treatment failure or last follow-up. Early treatment failure was defined as inability to achieve complete or partial remission (CR, PR), or documented progression/relapse after an initial CR/PR, during initial therapy or until the first post-treatment re-evaluation (usually at 1 month). Patients with toxic deaths during primary treatment were counted as events, but deaths in first remission, even if presumably attributed to long-term effects of treatment, were censored at the time of death. OS measured from treatment initiation to death from any cause was also analyzed. Survival curves were estimated with the Kaplan-Meier method. Median follow-up was estimated using the reverse Kaplan-Meier method (34).

The equality of distribution of baseline variables according to the chemotherapy regimen (R-CHOP-21 vs. R-CHOP-14) was evaluated by the chi-square test. Univariate survival analysis of FFP and OS was performed by the log-rank test (35). Multivariate analysis was performed in order to evaluate the potential independent prognostic significance of treatment with R-CHOP-21 vs. R-CHOP-14 after controlling for age (≥30 vs. <30 years), sex (male vs. female) and either the variables that were unequally distributed between the two treatment groups or the recently published by our group prognostic scores (6). All variables were entered into each multivariate model in order to adjust the effect of treatment regimen for the effect of all potentially confounding variables. The identification of independent prognostic factors was performed using Cox’s proportional hazards model (36).

Results

Patient characteristics. CIT was R-CHOP-21 in 310/339 patients (91.4%), while 29 patients (8.6%) received R-CHOP-14. The characteristics of the patients treated with R-CHOP-14 compared to those of the R-CHOP-21 are summarized in Table I. Briefly, patients who received R-CHOP-14 were slightly younger (median age 29 vs. 32 years; p=0.03, 59% of the patients in that group were <30 years old vs. 37% in the R-CHOP-21 group; p=0.025), had less frequently pericardial involvement (7% vs. 32%; p=0.005) and low serum albumin (26% vs. 48%; p=0.026) but marginally more frequently bulky disease (79% vs. 62%; p=0.085). Although LDH was elevated in similar percentages (90% vs. 82%; p=0.31), it was more frequently markedly elevated in R-CHOP-14-treated patients (≥2xULN in 52% vs. 25%; p=0.002). The above differences resulted in an imbalance in the distribution of patients across the E-IV/LDH model categories (p=0.024), with marginal differences regarding the E-IV/bulk model (p=0.144) and aaIPI score (p=0.063) as well, with R-CHOP-14-treated patients falling more frequently in the unfavorable categories.

Table I. Patient characteristics at diagnosis.

aaIPI: Age-adjusted International Prognostic Index; aaIPI_E: aaIPI considering the risk factor as “stage IV or stage IIE/IIIE”, but not stage III without extranodal involvement; ESR: erythrocyte sedimentation rate; LDH: serum lactate dehydrogenase; PS: ECOG performance status.

Treatment strategies. A minority of 19 (6%) among R-CHOP-21-treated patients received R-CHOP-21 variants as follows: substitution of doxorubicin with mitoxantrone (R-CNOP, 2 patients), substitution of doxorubicin with epirubicin (R-CEOP, 3 patients), substitution of doxorubicin with pegylated liposomal doxorubicin (R-lipoCHOP, 2 patients), addition of etoposide (R-CHOEP, 4 patients), platinum-based chemotherapy (3 patients) or high-dose methotrexate (2 patients) to R-CHOP, or administration of R-CHOP-21 for 1 cycle and then administration of infusional DA-EPOCH-R regimen (1 patient), or R-CHOP-21 for 4 cycles and then CHOP-21 for 4 additional cycles (1 patient), or administration of R-lipoCHOP for 1 cycle and then 5 additional cycles of R-COP-21 (R-CHOP-21 without doxorubicin, 1 patient). A similar minority of 3 patients (10%) among R-CHOP-14-treated patients also received R-CHOP-14 variants as follows: R-lipoCHOP (1 patient), R-CHOP-14 for 4 cycles and 4 additional cycles of R-CHOP-21 (1 patient), or R-CHOP-14 plus consolidation with autologous stem cell transplantation (ASCT, 1 patient).

In responding patients, RT was rather affected by PET/CT results in the PET era, as described above. Excluding patients with early treatment failure, RT was administered to 191/272 (70%) of R-CHOP-21-treated patients and 21/26 (81%) of R-CHOP-14-treated patients (p=0.26; Table II).

Table II. Comparison of outcomes between patients receiving R-CHOP-21 or R-CHOP-14.

CIT: Chemoimmunotherapy; FFP: freedom from progression; OS: overall survival; PD: progressive disease; PET: positron emission tomography; RT: radiotherapy. *Among 302 patients without early treatment failure; **Among 254 patients in the PET era (246 patients with available data, 8 patients with missing information); ***Among 189 of the 193 conventionally responding patients with PET evaluation directly after CIT, who had Deauville score available (missing in 4 patients); ****Among categories 1, 3, and 4 of “Post-treatment PET evaluation” (174+19+3+2+22+0=220), after the exclusion of the 4 patients with no Deauville score data available.

Patient outcomes. Patients treated with R-CHOP-21 had a similar early treatment failure rate compared to those treated with R-CHOP-14 [10.4% (32/307) vs. 6.9% (2/29); p=0.55] (Table II). The 5-year FFP and OS rates did not differ significantly between the two groups: R-CHOP-21- and R-CHOP-14-treated patients had a 5-year FFP rate of 77.9% vs. 79.3% respectively (p=0.89; Table II and Figure 1), while the corresponding 5-year OS rates were 89.0% vs. 85.6% (p=0.75; Table II and Figure 2).

Figure 1. Freedom from progression (FFP) according to chemotherapy regimen (R-CHOP-21 vs. R-CHOP-14).

Figure 2. Overall survival (OS) according to chemotherapy regimen (R-CHOP-21 vs. R-CHOP-14).

Among the 339 patients included in the present study, 254 had been treated in the PET era and 8 had missing data regarding PET/CT evaluation. With a similar rate of documented PD between the two arms, 174 and 19 patients treated with R-CHOP-21 and R-CHOP-14, respectively, were evaluated by EOT-PET among conventional responders to CIT. The distribution of the D5PSS was similar, as shown in Table II (p=0.40).

When the primary failure rate was evaluated in the PET era (defined as D5PSS-5 or conventionally documented PD), the proportion of corresponding patients was also similar: 21.9% (43/196) in the R-CHOP-21 vs. 15.0% (3/20) in the R-CHOP-14 group (p=0.47; Table II).

Multivariate analysis. In a multivariate analysis of prognostic factors regarding FFP, we initially examined a model including the treatment regimen, patients’ demographics, and 3 out of the 4 covariates that were unequally represented between the two treatment groups. Serum albumin was not included because of a relatively high rate of missing values. As shown in Table III, after adjustment for all these variables, R-CHOP-14 was associated with a 23% lower risk of treatment failure [hazard ratio (HR)=0.77, 95% confidence interval (CI)=0.30-2.01], which was not, however, statistically significant (p=0.59). Extranodal involvement was the only statistically significant factor (p=0.005), while markedly elevated LDH (≥2×ULN) was of borderline significance (p=0.093). When examined along with patients’ demographics and the E-IV/LDH model, R-CHOP-14 was associated with a 19% lower risk of treatment failure (HR=0.81, 95%CI=0.35-1.91), which was also not statistically significant (p=0.63; Table III). Similarly, when examined along with patients’ demographics and the E-IV/bulk model, R-CHOP-14 was associated with a statistically insignificant 15% lower risk of treatment failure (HR 0.85, 95%CI=0.34-2.13; p=0.72; Table III).

Table III. Multivariate analysis of FFP prognostic factors. The effect of R-CHOP-14 vs. R-CHOP-21 was adjusted for major prognostic factors, demographics, and variables unequally distributed between the two regimens (Model A) or established prognostic systems and demographics (Models B and C). All variables considered in each model are shown.

CI: Confidence interval; LDH: serum lactate dehydrogenase; ULN: upper limit of normal.

Regarding OS, when examined along with patients’ demographics and the E-IV/bulk model, R-CHOP-14 was associated with a 20% lower risk of treatment failure (HR=0.80, 95%CI=0.24-2.66), again without statistically significant difference (p=0.72; Table IV). Finally, when examined along with patients’ demographics and the E-IV/LDH model, R-CHOP-14 had absolutely no effect on the probability of survival (HR=1.03, 95%CI=0.36-2.99) (p=0.95; Table IV).

Table IV. Multivariate analysis of OS prognostic factors. The effect of R-CHOP-14 vs. R-CHOP-21 was adjusted for established prognostic systems and demographics. All variables that were considered in each model are shown.

CI: Confidence interval; LDH: serum lactate dehydrogenase; ULN: upper limit of normal.

Discussion

Although imperfect, the efficacy of CIT in the form of both R-CHOP-21 as well as R-CHOP-14 in PMLBCL has been well established with rather low rates of early treatment failure (3,4,6,18-21). However, the uncertainty about the superiority of any of these regimens still remains. Since median age at PMLBCL diagnosis is 35 years (2), the efficacy of standard chemotherapeutic regimens avoiding etoposide and more intensive treatments is reassuring regarding the development of secondary myeloid malignancies (7,37,38) and female patients’ fertility in particular (39). The shorter treatment duration with R-CHOP-14 may offer an advantage in terms of patients’ well-being, since it can impose a lighter physical, emotional, and psychological burden on them and their families and subsequently empower patient’s adherence to treatment, although relevant data exist only from patients with solid tumors (40-44). However, hematologic toxicity may also be higher with R-CHOP-14 compared to R-CHOP-21 (and requiring regular G-CSF prophylaxis), yet this may be less important in this young patient population (13-16).

Prospective data regarding R-CHOP-14in PMLBCL are very limited. Unplanned subgroup analyses of two randomized trials on aggressive lymphomas have provided rather conflicting data regarding the direct comparison between R-CHOP-21 and R-CHOP-14 in patients with PMLBCL. During the 2020 ASCO Annual Meeting, Held et al. presented the results of an unplanned subgroup analysis of the UNFOLDER randomized trial, in which younger patients (18-60 years old) with low or low-intermediate risk disease (aaIPI=0 plus bulk ≥7.5 cm or aaIPI=1) qualifying for RT to bulk or extralymphatic involvement (E) were randomized in a 2×2 factorial resign to receive 6 cycles of R-CHOP-21 or R-CHOP-14 with or without RT (45). In the subgroup of PMLBCL, 61 patients were randomized to receive R-CHOP-14 and 70 to receive R-CHOP-21, while 63% of the patients were randomly assigned to be consolidated with RT to bulk/E sites. Treatment densification with R-CHOP-14 in these low-risk patients did not improve EFS, PFS, or OS, with the latter being 96% at 3 years. However, the final results of this prospective trial have not been fully published yet.

In another unplanned (post hoc) subgroup analysis of the prospective UK National Cancer Research Institute, Gleeson et al. analyzed 50 patients with PMLBCL (19). All patients had stage II or bulky stage I, 92% were <60 years old and 84% had very low-risk disease according to the IPI with only 6% of the patients having an IPI score of 3. Interestingly, none of the patients had stage III/IV and, consequently, none had extensive extranodal disease. Among the 50 patients, 28 and 22 were randomized to receive either 8 cycles of R-CHOP-21 or 6 cycles of R-CHOP-14 plus 2 additional rituximab infusions. The overall response rate was 92% and 58% of all patients received consolidative RT. The 5-year PFS and OS were 80% and 84%, respectively (19). A non-significant improvement in PFS and OS with R-CHOP-14 compared to R-CHOP-21 was noticed: HR for PFS was 0.28 (95% CI=0.06-1.31, p=0.10), while HR for OS was 0.14 (95% CI=0.02-1.08, p=0.06). Although the absolute difference between the two subgroups was at least 20% for both PFS and OS, the small number of patients did not permit the emergence of statistical significance but also precluded the assessment of the impact of treatment regimen in a more objective manner with multivariate analysis. In line with the negative result of this trial in the whole aggressive B-cell lymphoma study population (13), the authors commented that no biological difference seemingly exists between PMLBCL and other aggressive B-cell lymphomas that could justify a better efficacy of a dose-dense regimen in PMLBCL patients compared to those with DLBCL (19). However, a favorable effect of R-CHOP-14 is suggested by these seemingly huge differences that in part contradicts the UNFOLDER subgroup analysis and stands in favor of a dedicated randomized trial to assess this question.

In a prospective study by Moskowitz et al. in which PMLBCL patients had been treated with a RT-free, dose-dense R-CHOP-14/ICE (ifosfamide, carboplatin, etoposide) regimen (with increased dose of cyclophosphamide), PFS and OS rates were 78% and 88%, respectively, at a median follow-up period of 3 years (46). These results do not appear better than those with R-CHOP, importantly however, they were achieved without RT.

More data are available from a few retrospective studies. Camus et al. have recently published the results of their multicenter retrospective study regarding PMLBCL patient outcomes after first-line treatment (21). Three hundred and thirteen patients were enrolled and received CIT, including R-CHOP-14 (n = 76) and R-CHOP-21 (n = 57). Overall, R-CHOP-14-treated patients had a more unfavourable disease profile (regarding LDH and IPI), yet only 3% of them were older than 60 years old (vs. 18% for R-CHOP-21-treated patients). The complete metabolic response (CMR, defined by a D5PSS of 1 to 3) rates were numerically but not statistically different after R-CHOP-14 and R-CHOP-21 (86.8% vs. 76.6%). With a median follow-up period of 44 months, patients treated with R-CHOP-14 had significantly better 3-year PFS (89.4% vs. 74.7%) and 3-year OS (100% vs. 87.5%) compared to those treated with R-CHOP-21, while adverse events were observed at a similar rate (21). Unfortunately, these differences cannot be easily interpreted, because 32% of patients treated with R-CHOP-14 received consolidation with ASCT vs. only 2% after R-CHOP-21, while 15% vs. 4% received consolidation RT, respectively, with both ASCT and RT being strong confounding factors. Furthermore, the multivariate analysis showed that treatment group was not associated with outcome and the inferior results of R-CHOP-21-treated patients were explained partly by a higher proportion of patients >60 years of age in this subgroup (21).

Martelli et al. presented the preliminary results of the IELSG-37 randomized trial on 545 PMLBCL patients analysing the end-of-treatment efficacy of various chemotherapeutic regimens, including R-CHOP-14 (n = 146, 27%) and R-CHOP-21 (n = 98, 18%) (20). Although the CMR rates were similar across the different treatment subgroups, the induction failure rate defined as D5PSS 5 was 25% with R-CHOP-21 vs. 7% with R-CHOP-14 and this may be crucial for treatment success.

Wästerlid et al. retrospectively identified 161 PMLBCL patients in the context of a real-life study of the Swedish Lymphoma Registry. The most popular regimen was R-CHOEP-14 (76 patients; 55% of the 137 patients with CIT regimen data available), which provided the best outcomes, but 26% of the patients had been treated with either R-CHOP-14 or R-CHOP-21; in fact, 33/36 of them had received R-CHOP-14 (47). R-CHOP-treated patients were older and administration of RT was very minimal, being limited to <20% of the patients. Two-year OS rate for all patients was 89% and 78% for patients treated with R-CHOP-21 or R-CHOP-14. In the multivariate analysis of OS, treatment with R-CHOP was associated with a HR of 3.6 compared to R-CHOEP. Updated results of this register study have also been recently published, according to which age was an adverse prognostic factor overall (48).

The above reported results are summarized in Table V and create a very complex picture regarding the relative efficacy of R-CHOP-14 and R-CHOP-21 in PMLBCL, which is confounded by differing baseline patient characteristics and use of consolidation strategies. In addition, the two randomized trials with available subgroup analyses have included only lower-risk patients. Moreover, the present study has failed to demonstrate a statistically significant difference in the efficacy of R-CHOP-14 and R-CHOP-21 in PMLBCL. However, treatment subgroups were heterogeneous regarding adverse prognostic factors, such as age and pericardial involvement (significantly older patients and commoner pericardial involvement in the R-CHOP-21 subgroup), or highly elevated LDH levels, extranodal stage IV and/or bulky disease (significantly more frequently observed in the R-CHOP-14 subgroup). Interestingly, our study included a significant proportion of PMLBCL patients with high-intermediate and high-risk disease (22% or 71/325 patients) as well as patients with very unfavourable characteristics, who had been excluded for example from the UNFOLDER and British randomized trial. After adjustment for potential confounding factors, R-CHOP-14 was associated with a 15-23% reduction in treatment failure rates, which was however totally insignificant from a statistical point of view.

Table V. PMLBCL studies regarding the comparison of R-CHOP-14 vs. R-CHOP-21.

*As approximated by the published survival curves. ASCT: Autologous stem cell transplantation; CMR: complete metabolic response; DS: Deauville score; diff.: difference; EFS: event-free survival; FFP: freedom from progression; HR: hazard ratio; LYSA: Lymphoma Study Association; ND: newly diagnosed; NR: not reported; n: number; pts: patients; OS: overall survival; PET(/CT): positron emission tomography(/computed tomography); PFS: progression-free survival; (R)-ACVBP: (rituximab)-doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisolone; R-CHOEP: rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisolone; R-CHOP-14 or -21:rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, administered every 14 or 21 days; REAL: Revised European-American Classification of Lymphoid Neoplasms; RT: radiotherapy; WHO: World Health Organization; yrs: years.

The interpretation of our results is limited by the low number of R-CHOP-14-treated patients and the non-randomized nature of the study. Although the results reported here do not support the a priori adoption of the dose-dense R-CHOP-14 in PMLBCL, a benefit of R-CHOP-14 cannot be excluded at all, especially in patients at higher-risk of treatment failure.

In conclusion, the absence of a statistically meaningful difference in terms of efficacy in our study adds to the uncertainty whether more intensive CIT regimens, and particularly R-CHOP-14, represent a better treatment option than the conventional R-CHOP-21 for PMLBCL patients. This issue can only be reliably addressed in the context of a randomized clinical trial. Meanwhile, novel salvage options as PD-1 inhibitors and CAR T cells and the possibility to incorporate PD-1 inhibitors into the first-line CIT regimens make the treatment landscape of PMLBCL even more complex (5,49-51).

Conflicts of Interest

The Authors declare that they have no conflicts of interest in relation to this study.

Authors’ Contributions

TPV conceived of and designed the study, conducted the statistical analysis, and contributed to the draft of the manuscript. SK contributed to the draft of the manuscript. All Authors equally contributed to data collection and critically reviewing the manuscript, and approved the final manuscript.