Haematology
Contributions
Type: Publication Only
Background
Thalidomide is an oral agent which has demonstrated significant anti-myeloma activity resulting in improved progression-free and overall survival rates in newly diagnosed multiple myeloma (MM) patients. The mechanisms of action of Thalidomide are complex and thought to include both antiangiogenic and immunomodulatory properties. However, as well as targeting neoplastic plasma cells, Thalidomide can affect other organ systems resulting in toxicities. These have been well documented and supportive measures are currently incorporated into our daily clinical practice to counteract these. However, there are other adverse effects which have been recorded as uncommon, including diverticular perforation. Recent figures have suggested that <1% patients treated between 2004-2012 reported this to the Food and Drugs Administration (FDA). However, contradictory to these findings, we have noticed an increasing number of patients within our trust presenting with this life-threatening complication. Furthermore, this complication has not been observed in patients receiving other types of anti-myeloma treatment, including Bortezomib, Lenalidomide and Bendamustine.
Aims
To study the association between Thalidomide and diverticular perforation in patients with Multiple Myeloma.
Methods
A retrospective case series was performed examining all MM patients who received Thalidomide, either as a single agent or in a combination regimen, between 1st January 2007 and 31st December 2014 at Epsom and St Helier Hospital. Patients who developed diverticular perforation while on Thalidomide were identified and further data collected. This included demographics, co-morbidities, disease response (according to the International Myeloma Working Group Response Criteria), time interval between current cycle of treatment and diverticular perforation, and patient outcome.
Results
A total 118 patients received Thalidomide of which 6 (5%) developed diverticular perforation. Interestingly, 3 of these patients had presented in the last 12 months. The median age for this group was 69 years (range 56-86 years) with equivalent numbers of males and females. None of the patients were known to suffer with gastrointestinal disease, although one patient did have associated renal amyloidosis.
All 6 patients received Thalidomide as part of a triplet regime with Dexamethasone and either Cyclophosphamide or Bortezomib for newly diagnosed multiple myeloma. The median number of cycles received was 4 (range 2.5 – 6) with 5 out of the 6 patients achieving a disease response. Response rates included 1 Complete Response (CR), 1 Very Good Partial Response (VGPR) and 3 PRs. Five patients received 100mg Thalidomide with 20mg Dexamethasone, while one patient was taking 200mg Thalidomide with 40mg Dexamethasone. All 6 patients were receiving thromboprophylaxis throughout their treatment.
Median time to presentation with diverticular perforation was 24 days (range 14-37) from day one of their current cycle. At presentation the median nadir neutrophil count was 5.1x109/L (range 1.1-14.4x109/L).
All 6 patients were managed surgically with subsequent bowel biopsies confirming diverticulitis. Five patients made a good post-operative recovery and were discharged. Three later received further treatment of which one patient was rechallenged with Thalidomide while the other two patients received Bortezomib instead. Two patients did not receive further treatment and are currently under active surveillance.
Summary
Our case series demonstrates that Thalidomide-associated diverticular perforation is far more prevalent than previously reported. Given the increasing use of this drug caution should be exercised by clinicians, particularly in patients with a known background of diverticular disease. Further research to establish the molecular mechanism by which Thalidomide induces diverticular perforation should be performed.
Keyword(s): Myeloma, Thalidomide, Toxicity
Type: Publication Only
Background
Thalidomide is an oral agent which has demonstrated significant anti-myeloma activity resulting in improved progression-free and overall survival rates in newly diagnosed multiple myeloma (MM) patients. The mechanisms of action of Thalidomide are complex and thought to include both antiangiogenic and immunomodulatory properties. However, as well as targeting neoplastic plasma cells, Thalidomide can affect other organ systems resulting in toxicities. These have been well documented and supportive measures are currently incorporated into our daily clinical practice to counteract these. However, there are other adverse effects which have been recorded as uncommon, including diverticular perforation. Recent figures have suggested that <1% patients treated between 2004-2012 reported this to the Food and Drugs Administration (FDA). However, contradictory to these findings, we have noticed an increasing number of patients within our trust presenting with this life-threatening complication. Furthermore, this complication has not been observed in patients receiving other types of anti-myeloma treatment, including Bortezomib, Lenalidomide and Bendamustine.
Aims
To study the association between Thalidomide and diverticular perforation in patients with Multiple Myeloma.
Methods
A retrospective case series was performed examining all MM patients who received Thalidomide, either as a single agent or in a combination regimen, between 1st January 2007 and 31st December 2014 at Epsom and St Helier Hospital. Patients who developed diverticular perforation while on Thalidomide were identified and further data collected. This included demographics, co-morbidities, disease response (according to the International Myeloma Working Group Response Criteria), time interval between current cycle of treatment and diverticular perforation, and patient outcome.
Results
A total 118 patients received Thalidomide of which 6 (5%) developed diverticular perforation. Interestingly, 3 of these patients had presented in the last 12 months. The median age for this group was 69 years (range 56-86 years) with equivalent numbers of males and females. None of the patients were known to suffer with gastrointestinal disease, although one patient did have associated renal amyloidosis.
All 6 patients received Thalidomide as part of a triplet regime with Dexamethasone and either Cyclophosphamide or Bortezomib for newly diagnosed multiple myeloma. The median number of cycles received was 4 (range 2.5 – 6) with 5 out of the 6 patients achieving a disease response. Response rates included 1 Complete Response (CR), 1 Very Good Partial Response (VGPR) and 3 PRs. Five patients received 100mg Thalidomide with 20mg Dexamethasone, while one patient was taking 200mg Thalidomide with 40mg Dexamethasone. All 6 patients were receiving thromboprophylaxis throughout their treatment.
Median time to presentation with diverticular perforation was 24 days (range 14-37) from day one of their current cycle. At presentation the median nadir neutrophil count was 5.1x109/L (range 1.1-14.4x109/L).
All 6 patients were managed surgically with subsequent bowel biopsies confirming diverticulitis. Five patients made a good post-operative recovery and were discharged. Three later received further treatment of which one patient was rechallenged with Thalidomide while the other two patients received Bortezomib instead. Two patients did not receive further treatment and are currently under active surveillance.
Summary
Our case series demonstrates that Thalidomide-associated diverticular perforation is far more prevalent than previously reported. Given the increasing use of this drug caution should be exercised by clinicians, particularly in patients with a known background of diverticular disease. Further research to establish the molecular mechanism by which Thalidomide induces diverticular perforation should be performed.
Keyword(s): Myeloma, Thalidomide, Toxicity