A phase 3 study of adding high-dose methotrexate/whole-brain radiotherapy to temozolomide to treatment-naïve PCNSL failed

Primary CNS lymphoma

Primary central nervous system lymphoma (PCNSL) is an aggressive, extranodal non-Hodgkin lymphoma whose standard regimen includes whole-brain radiation therapy (WBRT) and high-dose methotrexate (HD-MTX) sequential WBRT, with a median survival of 33 months
。 However, despite high initial complete response (CR) rates with HD-MTX sequential WBRT, more than 50% of patients relapse within the first two years of diagnosis; And due to increased neurotoxicity, 30 to 40 Gy WBRT is not suitable for all patients > 60 years of age
.

In addition, chemotherapy has limited efficacy due to the lack of effective blood-brain barrier penetration (BBB) and diffuse invasive growth of PCNSL, for example, R-CHOP plus WBRT has no better survival benefit than WBRT, mainly because BBB blocks penetration of most drugs (rituximab, doxorubicin, and vincristine
).
It is well known that PCNSL has a poor prognosis even after induction chemotherapy and complete remission of WBRT, and maintenance therapy that prolongs remission, delays recurrence, and maintains tumor dormancy may improve the efficacy
of PCNSL.

Temozolomide (TMZ) is an oral alkylating agent that penetrates the BBB and is moderately toxic, with some efficacy
in newly diagnosed and recurrent PCNSL 。 Therefore, Professor Kazuhiko Mishima of Saitama Medical University Hospital hypothesized that the inclusion of TMZ in HD-MTX and WBRT and TMZ maintenance therapy after radiotherapy improved disease control in PCNSL, and conducted a randomized, phase III study (JCOG1114C) to test the hypothesis that the addition of TMZ concomitant and maintenance chemotherapy to standard treatments for HD-MTX and WBRT improved survival in patients with newly diagnosed PCNSL – but the results were disappointing
。 The results were recently published in Neuro-Oncology
.

Study design

This is a randomized, open-label, phase III study involving 30 hospitals in Japan that enrolled the first newly diagnosed, non-immunocompromised PCNSL patients
。 Inclusion criteria included: age 20 to 70 years, histologically confirmed diffuse large B-cell lymphoma, disease confined to the CNS only (with or without intraocular lymphoma), absence of lymphomatic meningitis, absence of cerebral lymphoma disease, tumor biopsy or resection 3 to 35 days after surgery, ECOG of 0 to 2 (3 points allowed if due to neurological deficit), no previous chemotherapy or RT for any cancer, good organ function, etc
.

HD-MTX (3.
5 g/^m2, intravenous infusion for 3 hours) was given for 3 cycles on the first day of each cycle for 14 days/cycle, and adequate hydration, urine alkalinization, and folinic acid rescue
were given 24 hours after MTX 。 Response to HD-MTX was assessed by contrast-enhanced brain MRI 8 to 14 days after cycle 1 and 2 HD-MTX administration, and HD-MTX response by contrast-enhanced brain MRI, CSF cytology, slit lamp examination (mandatory for patients with ocular involvement), and corticosteroids 8 to 21 days after cycle 3 MTX administration
.
Mitigation assessment
using the International PCNSL Collaborative Group Mitigation Criteria.

Patients receiving at least 1 cycle of HD-MTX were randomized in a 1:1 ratio to receive either 30 Gy dose WBRT (for intracerebral parenchymal tumors after HD-MTX treatment) or 30 Gy dose WBRT + 10 Gy local enhancement (for positive intraparenchymal tumors) as a control (Group A), or WBRT± TMZ plus booster and TMZ maintenance therapy for two years as experimental therapy (Group B).

TMZ is administered concurrently with RT at a dose of 75 mg/^m2, starting on RT Day 1 and ending
on the last day of RT.
TMZ maintenance therapy (100-200 mg/^m2/day on days 1-5 every 4 weeks) is started 4 to 5 weeks after radiotherapy for 2 years (starting with HD-MTX).

Patients without visible intraparenchymal tumors after HD-MTX receive 15 sessions of 2 Gy WBRT, including the lower edge of the first segment of the cervical cord and two-thirds of the orbit, and in cases of ocular involvement, irradiation
of the eyeball.
For patients with visible intraparenchymal tumors following HD-MTX treatment, five comprehensive boosters of 2 Gy are given at the tumor area
.

The primary endpoint of this study was OS, defined as time
from 1:1 randomization to all-cause death or last contact to survivors.
Secondary endpoints were response rate after HD-MTX, response rate after radiotherapy, CR rate after HD-MTX, CR rate after radiotherapy, PFS, rate of adverse events, incidence of early death, incidence of treatment-related death, and rate of grade 4 non-haematological adverse events
.

Study results

122 patients were randomized, of which 62 and 60 were assigned to WBRT± local intensive radiotherapy (group A) and WBRT± local intensive radiotherapy plus TMZ + TMZ maintenance (group B), respectively, and the efficacy and safety
were analyzed.
The baseline characteristics were well balanced between the two groups (Table 1).

According to the results of the response assessment reviewed by the center, 14/52 (26.
9%) patients in group A achieved CR or unconfirmed CR (CRu, defined as minimal residual tumor on MRI) after HD-MTX treatment, a higher proportion than in group B (9/49 [18.
4%), while the proportion of PR and SD was similar between the two groups (PR: 48.
1% vs 49.
0%, SD: 13.
5% vs 12.
2%)
。 In addition, 10/49 (20.
4%) of patients in group B had PD, compared with group A (6/52 [11.
5%]).

One patient in group A was discontinued due to refusal during WBRT, and no patient discontinued therapy during group B RT plus TMZ
.
Six patients did not receive planned TMZ maintenance therapy (Figure 1), so 54 of 60 patients (90%) started TMZ maintenance therapy
.
During the maintenance treatment period, 41 patients were discontinued due to adverse events (n=5), disease progression (n=21), patient rejection due to adverse events (3 patients), death from unknown cause (1 patient), and early termination of study (11 patients), and only 13 patients completed the planned two-year maintenance therapy
.
The median period maintained by TMZ is 14.
5
.

RT response rates assessed by central review: CR/CRU in 29/52 cases (55.
8%) in group A and 17/49 (55.
1%) in group B, and the overall response rate after RT (CR/CRu + PR) was 96.
2% and 100%,
respectively.

toxicity

During HD-MTX treatment, grade 3 to 4 adverse events occurred in 69 of 133 patients (51.
9%), with lymphopenia being the most common grade 3- to 4 adverse event (22.
6%)
.
Other common grade 3-4 adverse events included neutropenia (12 cases, 9%), leukopenia (6 cases, 4.
5%), elevated ALT (17 patients, 12.
8%), hyponatremia (10 patients, 7.
5%), hypokalemia (6 cases, 4.
5%), and urinary tract infection (4 cases, 3%)
.

Table 2 shows adverse events
that occurred during RT.
The most common grade 3 to 4 adverse events were lymphopenia (18/60 [30%] in Group B and 7/61 [11.
5%] in Group A).

No treatment termination
due to adverse events during RT was observed in either group.

The most common grade 3- to 4 adverse events in the maintenance phase of group B were lymphopenia (24/54 [44.
4%]), fatigue (5/54 [9.
3%]), leukopenia (4/54 [7.
4%]), and neutropenia (2/54 [3.
7%]).

The high incidence of severe lymphopenia during TMZ plus RT may reflect combination therapy with TMZ with WBRT, while the high incidence of severe lymphopenia during maintenance therapy may reflect the long
duration of TMZ administration.

efficacy

In the June 2020 interim analysis, with a median follow-up of 1.
64 years, the 2-year OS was 86.
8% in group A and 71.
4% in group B (HR = 2.
18; P = 0.
97).

The study
was terminated early according to pre-specified stopping criteria due to invalid results.
The median PFS was 2.
6 years in group A and 1.
8 years in group B (HR = 1.
54).

In the updated analysis with a median follow-up of 3.
5 years in November 2021, there were a total of 122 patients, with a 2-year OS of 86.
7% in group A and 76.
2% in group B (Figure 2A).

The median PFS was 3.
5 years in group A and 2.
3 years in group B (Figure 2B).

The authors separately analyzed survival of patients with CR/CRu after HD-MTX induction (Table 3), and found that PFS and OS were identical
in CR/CRu patients in groups A and B.
In addition, they were classified by sex (male vs.
female), age (≤60 vs.
6≥1 years), residual enhanced tumors after HD-MTX treatment (no vs.
have), and MSKCC RPA (Class 1 vs.
61 years).
Class 2 vs.
Class 3) and OS comparisons between treatment groups found no subgroups that benefited from concomitant and maintenance therapy with TMZ (Table 3).

The Kaplan-Meier curve also showed no difference
in survival in patients with CR/CRu.

discuss

This is the first randomized trial of WBRT with or without radiotherapy augmentation, plus TMZ as concomitant and maintenance therapy after HD-MTX, and the authors of this randomized, phase III study confirmed that the addition of TMZ concomitant and maintenance therapy to standard treatment of HD-MTX and WBRT did not improve OS and PFS
in patients with newly diagnosed PCNSL.
Given the lack of clinical benefit in the TMZ treatment group, TMZ was discontinued in all patients still receiving protocol-prescribed therapy in this study – but in fact this result was not expected
.

It has previously been reported that maintenance therapy with WBRT and 10 months after exposure to TMZ maintenance therapy for HD-MTX, rituximab, and TMZ induction chemotherapy in patients with PCNSL can be extended for 2 years PFS and OS
.
Since TMZ has been used in clinical trials and is considered an important drug for PCNSL therapeutic development, it is both disappointing and intriguing that this study found TMZ to be ineffective in consolidation and maintenance therapy for PCNSL
.

Several explanations
for these unintended results can be proposed.
First, the most likely reason for differences in survival outcomes may be TMZ treatment-related adverse events such as severe lymphopenia: grade 3-4 lymphopenia was observed in 30% of patients during WBRT+ concomitant TMZ therapy, and grade 3-4 lymphopenia
was observed in 44.
4% of patients during maintenance TMZ therapy 。 Lymphopenia may be a biomarker of impaired host immunity in cancer patients, as studies have shown that low absolute lymphocyte count is associated with poor outcomes in patients with lymphoma and other cancers; Although the underlying mechanisms and causes of lymphopenia associated with poorer OS and PFS outcomes in PCNSL patients are unclear, lymphopenia may be associated with inadequate cytokine production, which stimulates chemokine production, leading to reduced
antitumor immunity.
A second possible cause may be an imbalance in CR rates between groups after induction of HD-MTX (26.
9% in group A compared to 18.
4% in group B).

However, this is a weak hypothesis, as no significant additive effect
of TMZ has been demonstrated in the subgroup of CR patients after HD-MTX treatment.

References

Kazuhiko Mishima,et al.
Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly diagnosed primary CNS lymphoma: JCOG1114C.
Neuro Oncol .
2022 Nov 5; noac246.
doi: 10.
1093/neuonc/noac246.

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