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Primary CNS lymphoma: R-CHOP hits back
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.
Fighting in a passive manner active against Clostridium difficile
Infections resulting from Clostridium difficile are a major clinical challenge. In hematology and oncology, the widespread use of broad-spectrum antibiotics is essential for patients with profound neutropenia and infectious complications, which are a high-risk factor for C. difficile enteritis.
C. difficile enteritis occurs in 5%-20% of cancer patients.1 With standard of care antibiotics, oral metronidazole or oral vancomycin, high C. difficile cure rates are possible, but up to 25% of these infections recur. Recently, oral fidaxomicin was approved for treatment of C. difficile enteritis and was associated with high cure rates and, more importantly, with significantly lower recurrence rates.2
Bezlotoxumab, a fully humanized monoclonal antibody against C. difficile toxin B, has been shown by x-ray crystallography to neutralize toxin B by blocking its ability to bind to host cells.7 Most recently, this new therapeutic approach was investigated in humans.8
Wilcox et al. used pooled data of 2655 adults treated in two double-blind, randomized, placebo-controlled phase III clinical trials (MODIFY I and MODIFY II) for primary or recurrent C. difficile enteritis. This industry-sponsored trial was conducted at 322 sites in 30 countries.
In one treatment group, patients received a single infusion of bezlotoxumab (781 patients) or placebo (773 patients) and one of the three oral standard-of-care C. difficile antibiotics. Importantly, the primary end point of this trial was recurrent infection within 12 weeks. About 28% of the patients in both the bezlotoxumab group and the placebo group previously had at least one episode of C. difficile enteritis. About 20% of the patients in both groups were immunocompromised.
Pooled data showed that recurrent infection was significantly lower (P less than 0.001) in the bezlotoxumab group (17%), compared with the placebo group (27%). The difference in recurrence rate (25% vs. 41%) was even more pronounced in patients with one or more episodes of recurrent C. difficile enteritis in the past 6 months. Furthermore, a benefit for bezlotoxumab was seen in immunocompromised patients, whose recurrence rates were 15% with bezlotoxumab, vs. 28% with placebo. After the 12 weeks of follow-up, the absolute difference in the Kaplan-Meier rates of recurrent infection was 13% (absolute rate, 21% in bezlotoxumab group vs. 34% in placebo group; P less than 0.001).
The results indicate that bezlotoxumab, which was approved in 2016 by the U.S. Food and Drug Administration, might improve the outcome of patients with C. difficile enteritis. However, bezlotoxumab is not a “magic bullet.” The number needed to treat to prevent one episode of C. difficile enteritis is 10.
It is conceivable that bezlotoxumab may find its role in high-risk patients – those older than 65 years or patients with recurrent C. difficile enteritis – since the number needed to treat is only 6 in these subgroups.8
This new agent could be an important treatment option for our high-risk patients in hematology. However, more studies concerning costs and real-life efficacy are needed.
The new approach of passive immunization for prevention of recurrent C. difficile enteritis shows the importance and the role of toxin B – not only the bacterium per se – in pathogenesis and virulence of C. difficile. This could mean that we have to renew our view on the role of antibiotics against C. difficile. However, in contrast, bezlotoxumab does not affect the efficacy of standard of care antibiotics since the initial cure rates were 80% for both the antibody and the placebo groups.8 Toxin B levels are not detectable in stool samples between days 4 and 10 of standard of care antibiotic treatment. Afterward, however, they increase again.9 Most of the patients had received bezlotoxumab 3 or more days after they began standard-of-care antibiotic treatment – in the time period when toxin B is undetectable in stool – which underlines the importance of toxin B in the pathogenesis of recurrent C. difficile enteritis.8
In summary, the introduction of bezlotoxumab in clinical care gives new and important insights and solutions not only for treatment options but also for our understanding of C. difficile pathogenesis.
Dr. Schalk is consultant of internal medicine at the department of hematology and oncology, Magdeburg University Hospital, Germany, with clinical and research focus on infectious diseases in hematology and oncology.
Dr. Fischer is professor of internal medicine, hematology and oncology, at the Otto-von-Guericke University Hospital Magdeburg, Germany. He is head of the department of hematology and oncology and a clinical/molecular researcher in myeloid neoplasms. He is a member of the editorial advisory board of Hematology News.
Contact Dr. Schalk at enrico.schalk@med.ovgu.de.
References
1. Vehreschild, MJ et al. Diagnosis and management of gastrointestinal complications in adult cancer patients: Wvidence-based guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Oncol. 2013;24:1189-202
2. Cornely, OA. Current and emerging management options for Clostridium difficile infection: What is the role of fidaxomicin? Clin Microbiol Infect. 2012;18(Suppl 6):28-35.
3. Bartlett, JG et al. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med. 1978;298(10):531-4.
4. Lyras, D et al. Toxin B is essential for virulence of Clostridium difficile. Nature. 2009;458:1176-9.
5. Reineke, J et al. Autocatalytic cleavage of Clostridium difficile toxin B. Nature. 2007;446:415-9.
6. Leav, BA et al. Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine. 2010;28:965-9.
7. Orth, P et al. Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem. 2014;289:18008-21.
8. Wilcox, MH et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305-17.
9. Louie, TJ et al. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis. 2012;5(Suppl 2):S132-42.
Infections resulting from Clostridium difficile are a major clinical challenge. In hematology and oncology, the widespread use of broad-spectrum antibiotics is essential for patients with profound neutropenia and infectious complications, which are a high-risk factor for C. difficile enteritis.
C. difficile enteritis occurs in 5%-20% of cancer patients.1 With standard of care antibiotics, oral metronidazole or oral vancomycin, high C. difficile cure rates are possible, but up to 25% of these infections recur. Recently, oral fidaxomicin was approved for treatment of C. difficile enteritis and was associated with high cure rates and, more importantly, with significantly lower recurrence rates.2
Bezlotoxumab, a fully humanized monoclonal antibody against C. difficile toxin B, has been shown by x-ray crystallography to neutralize toxin B by blocking its ability to bind to host cells.7 Most recently, this new therapeutic approach was investigated in humans.8
Wilcox et al. used pooled data of 2655 adults treated in two double-blind, randomized, placebo-controlled phase III clinical trials (MODIFY I and MODIFY II) for primary or recurrent C. difficile enteritis. This industry-sponsored trial was conducted at 322 sites in 30 countries.
In one treatment group, patients received a single infusion of bezlotoxumab (781 patients) or placebo (773 patients) and one of the three oral standard-of-care C. difficile antibiotics. Importantly, the primary end point of this trial was recurrent infection within 12 weeks. About 28% of the patients in both the bezlotoxumab group and the placebo group previously had at least one episode of C. difficile enteritis. About 20% of the patients in both groups were immunocompromised.
Pooled data showed that recurrent infection was significantly lower (P less than 0.001) in the bezlotoxumab group (17%), compared with the placebo group (27%). The difference in recurrence rate (25% vs. 41%) was even more pronounced in patients with one or more episodes of recurrent C. difficile enteritis in the past 6 months. Furthermore, a benefit for bezlotoxumab was seen in immunocompromised patients, whose recurrence rates were 15% with bezlotoxumab, vs. 28% with placebo. After the 12 weeks of follow-up, the absolute difference in the Kaplan-Meier rates of recurrent infection was 13% (absolute rate, 21% in bezlotoxumab group vs. 34% in placebo group; P less than 0.001).
The results indicate that bezlotoxumab, which was approved in 2016 by the U.S. Food and Drug Administration, might improve the outcome of patients with C. difficile enteritis. However, bezlotoxumab is not a “magic bullet.” The number needed to treat to prevent one episode of C. difficile enteritis is 10.
It is conceivable that bezlotoxumab may find its role in high-risk patients – those older than 65 years or patients with recurrent C. difficile enteritis – since the number needed to treat is only 6 in these subgroups.8
This new agent could be an important treatment option for our high-risk patients in hematology. However, more studies concerning costs and real-life efficacy are needed.
The new approach of passive immunization for prevention of recurrent C. difficile enteritis shows the importance and the role of toxin B – not only the bacterium per se – in pathogenesis and virulence of C. difficile. This could mean that we have to renew our view on the role of antibiotics against C. difficile. However, in contrast, bezlotoxumab does not affect the efficacy of standard of care antibiotics since the initial cure rates were 80% for both the antibody and the placebo groups.8 Toxin B levels are not detectable in stool samples between days 4 and 10 of standard of care antibiotic treatment. Afterward, however, they increase again.9 Most of the patients had received bezlotoxumab 3 or more days after they began standard-of-care antibiotic treatment – in the time period when toxin B is undetectable in stool – which underlines the importance of toxin B in the pathogenesis of recurrent C. difficile enteritis.8
In summary, the introduction of bezlotoxumab in clinical care gives new and important insights and solutions not only for treatment options but also for our understanding of C. difficile pathogenesis.
Dr. Schalk is consultant of internal medicine at the department of hematology and oncology, Magdeburg University Hospital, Germany, with clinical and research focus on infectious diseases in hematology and oncology.
Dr. Fischer is professor of internal medicine, hematology and oncology, at the Otto-von-Guericke University Hospital Magdeburg, Germany. He is head of the department of hematology and oncology and a clinical/molecular researcher in myeloid neoplasms. He is a member of the editorial advisory board of Hematology News.
Contact Dr. Schalk at enrico.schalk@med.ovgu.de.
References
1. Vehreschild, MJ et al. Diagnosis and management of gastrointestinal complications in adult cancer patients: Wvidence-based guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Oncol. 2013;24:1189-202
2. Cornely, OA. Current and emerging management options for Clostridium difficile infection: What is the role of fidaxomicin? Clin Microbiol Infect. 2012;18(Suppl 6):28-35.
3. Bartlett, JG et al. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med. 1978;298(10):531-4.
4. Lyras, D et al. Toxin B is essential for virulence of Clostridium difficile. Nature. 2009;458:1176-9.
5. Reineke, J et al. Autocatalytic cleavage of Clostridium difficile toxin B. Nature. 2007;446:415-9.
6. Leav, BA et al. Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine. 2010;28:965-9.
7. Orth, P et al. Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem. 2014;289:18008-21.
8. Wilcox, MH et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305-17.
9. Louie, TJ et al. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis. 2012;5(Suppl 2):S132-42.
Infections resulting from Clostridium difficile are a major clinical challenge. In hematology and oncology, the widespread use of broad-spectrum antibiotics is essential for patients with profound neutropenia and infectious complications, which are a high-risk factor for C. difficile enteritis.
C. difficile enteritis occurs in 5%-20% of cancer patients.1 With standard of care antibiotics, oral metronidazole or oral vancomycin, high C. difficile cure rates are possible, but up to 25% of these infections recur. Recently, oral fidaxomicin was approved for treatment of C. difficile enteritis and was associated with high cure rates and, more importantly, with significantly lower recurrence rates.2
Bezlotoxumab, a fully humanized monoclonal antibody against C. difficile toxin B, has been shown by x-ray crystallography to neutralize toxin B by blocking its ability to bind to host cells.7 Most recently, this new therapeutic approach was investigated in humans.8
Wilcox et al. used pooled data of 2655 adults treated in two double-blind, randomized, placebo-controlled phase III clinical trials (MODIFY I and MODIFY II) for primary or recurrent C. difficile enteritis. This industry-sponsored trial was conducted at 322 sites in 30 countries.
In one treatment group, patients received a single infusion of bezlotoxumab (781 patients) or placebo (773 patients) and one of the three oral standard-of-care C. difficile antibiotics. Importantly, the primary end point of this trial was recurrent infection within 12 weeks. About 28% of the patients in both the bezlotoxumab group and the placebo group previously had at least one episode of C. difficile enteritis. About 20% of the patients in both groups were immunocompromised.
Pooled data showed that recurrent infection was significantly lower (P less than 0.001) in the bezlotoxumab group (17%), compared with the placebo group (27%). The difference in recurrence rate (25% vs. 41%) was even more pronounced in patients with one or more episodes of recurrent C. difficile enteritis in the past 6 months. Furthermore, a benefit for bezlotoxumab was seen in immunocompromised patients, whose recurrence rates were 15% with bezlotoxumab, vs. 28% with placebo. After the 12 weeks of follow-up, the absolute difference in the Kaplan-Meier rates of recurrent infection was 13% (absolute rate, 21% in bezlotoxumab group vs. 34% in placebo group; P less than 0.001).
The results indicate that bezlotoxumab, which was approved in 2016 by the U.S. Food and Drug Administration, might improve the outcome of patients with C. difficile enteritis. However, bezlotoxumab is not a “magic bullet.” The number needed to treat to prevent one episode of C. difficile enteritis is 10.
It is conceivable that bezlotoxumab may find its role in high-risk patients – those older than 65 years or patients with recurrent C. difficile enteritis – since the number needed to treat is only 6 in these subgroups.8
This new agent could be an important treatment option for our high-risk patients in hematology. However, more studies concerning costs and real-life efficacy are needed.
The new approach of passive immunization for prevention of recurrent C. difficile enteritis shows the importance and the role of toxin B – not only the bacterium per se – in pathogenesis and virulence of C. difficile. This could mean that we have to renew our view on the role of antibiotics against C. difficile. However, in contrast, bezlotoxumab does not affect the efficacy of standard of care antibiotics since the initial cure rates were 80% for both the antibody and the placebo groups.8 Toxin B levels are not detectable in stool samples between days 4 and 10 of standard of care antibiotic treatment. Afterward, however, they increase again.9 Most of the patients had received bezlotoxumab 3 or more days after they began standard-of-care antibiotic treatment – in the time period when toxin B is undetectable in stool – which underlines the importance of toxin B in the pathogenesis of recurrent C. difficile enteritis.8
In summary, the introduction of bezlotoxumab in clinical care gives new and important insights and solutions not only for treatment options but also for our understanding of C. difficile pathogenesis.
Dr. Schalk is consultant of internal medicine at the department of hematology and oncology, Magdeburg University Hospital, Germany, with clinical and research focus on infectious diseases in hematology and oncology.
Dr. Fischer is professor of internal medicine, hematology and oncology, at the Otto-von-Guericke University Hospital Magdeburg, Germany. He is head of the department of hematology and oncology and a clinical/molecular researcher in myeloid neoplasms. He is a member of the editorial advisory board of Hematology News.
Contact Dr. Schalk at enrico.schalk@med.ovgu.de.
References
1. Vehreschild, MJ et al. Diagnosis and management of gastrointestinal complications in adult cancer patients: Wvidence-based guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Oncol. 2013;24:1189-202
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