Vanja Zeremski, MD

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma solely confined to the CNS. The majority of PCNSL histologically presents as diffuse large B-cell lymphoma (DLBCL). However, outcomes in these patients are notably inferior, compared with nodal or other extranodal DLBCL. In order to achieve long-term progression-free survival, high-dose methotrexate (HD-MTX)–based chemotherapy followed by consolidation is needed. However, this treatment is associated with high toxicity burden and it is restricted to a select patient population – the young and fit – and requires administration at specialized hematological centers.

In the 1990s, the conventional DLBCL treatment regimen with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was tested in PCNSL patients. The results were rather disappointing. The addition of CHOP to whole brain radiation or HD-MTX could not improve survival.^1-3 The reason for CHOP failure was poor CNS penetration of doxorubicin and cyclophosphamide because of their high molecular weight. Consequently, it was concluded that there is no role for CHOP-like chemotherapy in the treatment of PCNSL.⁴

But is this really the case? Twenty years later, this traditional view has been challenged by Andres J.M. Ferreri, MD, and colleagues in the INGRID trial.⁵ Dr. Ferreri presented findings from the trial at the International Conference on Malignant Lymphoma in Lugano, Switzerland, which was greeted with much excitement.⁶

INGRID is a phase 2 trial conducted on patients with refractory/relapsed PCNSL. It consisted of a CHOP plus rituximab (R-CHOP) regimen, which was upgraded by engineered tumor necrosis factor–alpha (TNF-alpha). The idea was to enhance the blood-brain barrier (BBB) permeability and consequently improve the efficacy of R-CHOP in PCNSL. The use of human TNF-alpha is limited by relevant toxicities. In order to avoid that, a fusion of human TNF-alpha and CNGRCG peptide (called NGR-TNF) was developed.

CNGRCG peptide is a ligand of CD13, an aminopeptidase that is expressed almost exclusively on tumor blood vessels. Preclinical data showed that binding of CNGRCG to CD13 results in targeted – local, not systemic – delivery of TNF-alpha to the tumor blood vessels. Consequently, TNF-alpha led to increased vascular permeability in tumor tissue and enabled higher penetration of chemotherapeutic agents.^7,8

Altogether, 12 heavily pretreated PCNSL patients were included in the INGRID trial. Seven patients had two or more previous treatment regimens. Within this trial, patients received R-CHOP with NGR-TNF (0.8 mcg/m²) applied 2 hours prior to R-CHOP. The great majority of grade 3/4 adverse events were hematological toxicities. Importantly, no neurological side effects of any grade occurred.

The primary aim of this study was to investigate the CD13 expression on tumor tissue and provide a proof of concept for the use of NGR-TNF/R-CHOP. Indeed, CD13 expression was observed on tumor vessels in all patients. Consequently, increased BBB permeability in tumor tissue after NGR-TNF infusion was observed using dynamic contrast-enhanced MRI and by brain scintigraphy (SPECT). This was assessed 1 day after NGR-TNF/R-CHOP treatment. More importantly, this effect on BBB seems to be sustained because it was also observed after the last cycle of NGR-TNF/R-CHOP. The fact that there was no change of drug concentrations of R-CHOP components in plasma or cerebrospinal fluid suggests that the effect of NGR-TNF is restricted to tumor vessels.

The authors also reported preliminary results regarding response rates to NGR-TNF/R-CHOP. The overall response rate was 75%. Of note, six patients achieved complete remission and one patient achieved a partial remission. The median duration of response was 10 months (range, 7-14 months), and nine patients were able to proceed to consolidation treatment.

These preliminary results are encouraging and open a new window for the treatment strategies in PCNSL patients. NGR-TNF/R-CHOP treatment induced responses in 75% of these heavily pretreated patients. The low toxicity profile and feasibility of this regimen could allow clinicians to carry out this treatment approach in outpatient settings, as well as in older and comorbid patients. Extensive supportive therapy – such as intensive hydration or leucovorin-rescue by HD-MTX – is not needed.

These results will need to be confirmed through testing in a larger patient population. Dr. Ferreri and colleagues are currently conducting the extended phase of this study and aim to recruit 28 patients. If they report positive results from that study, evaluation of NGR-TNF/R-CHOP as a first-line treatment of PCNSL seems to be the next reasonable step.

Dr. Zeremski and Dr. Fischer are both in the department of hematology/oncology and affiliated with the Health Campus Immunology, Infectiology and Inflammation at Otto-von-Guericke University Magdeburg (Germany). Dr. Fischer is a member of the editorial advisory board of Hematology News. The authors reported having no conflicts of interest.

References

1. J Clin Oncol. 1996;14:556-64.

2. Cancer. 2000;89:1359-70.

3. J Neurooncol. 1996;30:257-65.

4. Guidelines on the diagnosis and management of adult patients with primary CNS lymphoma (PCNSL) and primary intra-ocular lymphoma (PIOL). British Society for Haematology/British Committee for Standards in Haematology; HO/016, 2009.

5. Blood. 2019;134:252-62.

6. Hematol Oncol. 2019; 37:159.

7. BioDrugs. 2013;27:591-603.

8. J Clin Invest. 2002;110:475-82.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma solely confined to the CNS. The majority of PCNSL histologically presents as diffuse large B-cell lymphoma (DLBCL). However, outcomes in these patients are notably inferior, compared with nodal or other extranodal DLBCL. In order to achieve long-term progression-free survival, high-dose methotrexate (HD-MTX)–based chemotherapy followed by consolidation is needed. However, this treatment is associated with high toxicity burden and it is restricted to a select patient population – the young and fit – and requires administration at specialized hematological centers.

In the 1990s, the conventional DLBCL treatment regimen with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was tested in PCNSL patients. The results were rather disappointing. The addition of CHOP to whole brain radiation or HD-MTX could not improve survival.^1-3 The reason for CHOP failure was poor CNS penetration of doxorubicin and cyclophosphamide because of their high molecular weight. Consequently, it was concluded that there is no role for CHOP-like chemotherapy in the treatment of PCNSL.⁴

But is this really the case? Twenty years later, this traditional view has been challenged by Andres J.M. Ferreri, MD, and colleagues in the INGRID trial.⁵ Dr. Ferreri presented findings from the trial at the International Conference on Malignant Lymphoma in Lugano, Switzerland, which was greeted with much excitement.⁶

INGRID is a phase 2 trial conducted on patients with refractory/relapsed PCNSL. It consisted of a CHOP plus rituximab (R-CHOP) regimen, which was upgraded by engineered tumor necrosis factor–alpha (TNF-alpha). The idea was to enhance the blood-brain barrier (BBB) permeability and consequently improve the efficacy of R-CHOP in PCNSL. The use of human TNF-alpha is limited by relevant toxicities. In order to avoid that, a fusion of human TNF-alpha and CNGRCG peptide (called NGR-TNF) was developed.

CNGRCG peptide is a ligand of CD13, an aminopeptidase that is expressed almost exclusively on tumor blood vessels. Preclinical data showed that binding of CNGRCG to CD13 results in targeted – local, not systemic – delivery of TNF-alpha to the tumor blood vessels. Consequently, TNF-alpha led to increased vascular permeability in tumor tissue and enabled higher penetration of chemotherapeutic agents.^7,8

Altogether, 12 heavily pretreated PCNSL patients were included in the INGRID trial. Seven patients had two or more previous treatment regimens. Within this trial, patients received R-CHOP with NGR-TNF (0.8 mcg/m²) applied 2 hours prior to R-CHOP. The great majority of grade 3/4 adverse events were hematological toxicities. Importantly, no neurological side effects of any grade occurred.

The primary aim of this study was to investigate the CD13 expression on tumor tissue and provide a proof of concept for the use of NGR-TNF/R-CHOP. Indeed, CD13 expression was observed on tumor vessels in all patients. Consequently, increased BBB permeability in tumor tissue after NGR-TNF infusion was observed using dynamic contrast-enhanced MRI and by brain scintigraphy (SPECT). This was assessed 1 day after NGR-TNF/R-CHOP treatment. More importantly, this effect on BBB seems to be sustained because it was also observed after the last cycle of NGR-TNF/R-CHOP. The fact that there was no change of drug concentrations of R-CHOP components in plasma or cerebrospinal fluid suggests that the effect of NGR-TNF is restricted to tumor vessels.

The authors also reported preliminary results regarding response rates to NGR-TNF/R-CHOP. The overall response rate was 75%. Of note, six patients achieved complete remission and one patient achieved a partial remission. The median duration of response was 10 months (range, 7-14 months), and nine patients were able to proceed to consolidation treatment.

These preliminary results are encouraging and open a new window for the treatment strategies in PCNSL patients. NGR-TNF/R-CHOP treatment induced responses in 75% of these heavily pretreated patients. The low toxicity profile and feasibility of this regimen could allow clinicians to carry out this treatment approach in outpatient settings, as well as in older and comorbid patients. Extensive supportive therapy – such as intensive hydration or leucovorin-rescue by HD-MTX – is not needed.

These results will need to be confirmed through testing in a larger patient population. Dr. Ferreri and colleagues are currently conducting the extended phase of this study and aim to recruit 28 patients. If they report positive results from that study, evaluation of NGR-TNF/R-CHOP as a first-line treatment of PCNSL seems to be the next reasonable step.

Dr. Zeremski and Dr. Fischer are both in the department of hematology/oncology and affiliated with the Health Campus Immunology, Infectiology and Inflammation at Otto-von-Guericke University Magdeburg (Germany). Dr. Fischer is a member of the editorial advisory board of Hematology News. The authors reported having no conflicts of interest.

References

1. J Clin Oncol. 1996;14:556-64.

2. Cancer. 2000;89:1359-70.

3. J Neurooncol. 1996;30:257-65.

4. Guidelines on the diagnosis and management of adult patients with primary CNS lymphoma (PCNSL) and primary intra-ocular lymphoma (PIOL). British Society for Haematology/British Committee for Standards in Haematology; HO/016, 2009.

5. Blood. 2019;134:252-62.

6. Hematol Oncol. 2019; 37:159.

7. BioDrugs. 2013;27:591-603.

8. J Clin Invest. 2002;110:475-82.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma solely confined to the CNS. The majority of PCNSL histologically presents as diffuse large B-cell lymphoma (DLBCL). However, outcomes in these patients are notably inferior, compared with nodal or other extranodal DLBCL. In order to achieve long-term progression-free survival, high-dose methotrexate (HD-MTX)–based chemotherapy followed by consolidation is needed. However, this treatment is associated with high toxicity burden and it is restricted to a select patient population – the young and fit – and requires administration at specialized hematological centers.

In the 1990s, the conventional DLBCL treatment regimen with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was tested in PCNSL patients. The results were rather disappointing. The addition of CHOP to whole brain radiation or HD-MTX could not improve survival.^1-3 The reason for CHOP failure was poor CNS penetration of doxorubicin and cyclophosphamide because of their high molecular weight. Consequently, it was concluded that there is no role for CHOP-like chemotherapy in the treatment of PCNSL.⁴

But is this really the case? Twenty years later, this traditional view has been challenged by Andres J.M. Ferreri, MD, and colleagues in the INGRID trial.⁵ Dr. Ferreri presented findings from the trial at the International Conference on Malignant Lymphoma in Lugano, Switzerland, which was greeted with much excitement.⁶

INGRID is a phase 2 trial conducted on patients with refractory/relapsed PCNSL. It consisted of a CHOP plus rituximab (R-CHOP) regimen, which was upgraded by engineered tumor necrosis factor–alpha (TNF-alpha). The idea was to enhance the blood-brain barrier (BBB) permeability and consequently improve the efficacy of R-CHOP in PCNSL. The use of human TNF-alpha is limited by relevant toxicities. In order to avoid that, a fusion of human TNF-alpha and CNGRCG peptide (called NGR-TNF) was developed.

CNGRCG peptide is a ligand of CD13, an aminopeptidase that is expressed almost exclusively on tumor blood vessels. Preclinical data showed that binding of CNGRCG to CD13 results in targeted – local, not systemic – delivery of TNF-alpha to the tumor blood vessels. Consequently, TNF-alpha led to increased vascular permeability in tumor tissue and enabled higher penetration of chemotherapeutic agents.^7,8

Altogether, 12 heavily pretreated PCNSL patients were included in the INGRID trial. Seven patients had two or more previous treatment regimens. Within this trial, patients received R-CHOP with NGR-TNF (0.8 mcg/m²) applied 2 hours prior to R-CHOP. The great majority of grade 3/4 adverse events were hematological toxicities. Importantly, no neurological side effects of any grade occurred.

The primary aim of this study was to investigate the CD13 expression on tumor tissue and provide a proof of concept for the use of NGR-TNF/R-CHOP. Indeed, CD13 expression was observed on tumor vessels in all patients. Consequently, increased BBB permeability in tumor tissue after NGR-TNF infusion was observed using dynamic contrast-enhanced MRI and by brain scintigraphy (SPECT). This was assessed 1 day after NGR-TNF/R-CHOP treatment. More importantly, this effect on BBB seems to be sustained because it was also observed after the last cycle of NGR-TNF/R-CHOP. The fact that there was no change of drug concentrations of R-CHOP components in plasma or cerebrospinal fluid suggests that the effect of NGR-TNF is restricted to tumor vessels.

The authors also reported preliminary results regarding response rates to NGR-TNF/R-CHOP. The overall response rate was 75%. Of note, six patients achieved complete remission and one patient achieved a partial remission. The median duration of response was 10 months (range, 7-14 months), and nine patients were able to proceed to consolidation treatment.

These preliminary results are encouraging and open a new window for the treatment strategies in PCNSL patients. NGR-TNF/R-CHOP treatment induced responses in 75% of these heavily pretreated patients. The low toxicity profile and feasibility of this regimen could allow clinicians to carry out this treatment approach in outpatient settings, as well as in older and comorbid patients. Extensive supportive therapy – such as intensive hydration or leucovorin-rescue by HD-MTX – is not needed.

These results will need to be confirmed through testing in a larger patient population. Dr. Ferreri and colleagues are currently conducting the extended phase of this study and aim to recruit 28 patients. If they report positive results from that study, evaluation of NGR-TNF/R-CHOP as a first-line treatment of PCNSL seems to be the next reasonable step.

Dr. Zeremski and Dr. Fischer are both in the department of hematology/oncology and affiliated with the Health Campus Immunology, Infectiology and Inflammation at Otto-von-Guericke University Magdeburg (Germany). Dr. Fischer is a member of the editorial advisory board of Hematology News. The authors reported having no conflicts of interest.

References

1. J Clin Oncol. 1996;14:556-64.

2. Cancer. 2000;89:1359-70.

3. J Neurooncol. 1996;30:257-65.

4. Guidelines on the diagnosis and management of adult patients with primary CNS lymphoma (PCNSL) and primary intra-ocular lymphoma (PIOL). British Society for Haematology/British Committee for Standards in Haematology; HO/016, 2009.

5. Blood. 2019;134:252-62.

6. Hematol Oncol. 2019; 37:159.

7. BioDrugs. 2013;27:591-603.

8. J Clin Invest. 2002;110:475-82.