Acetyl-l-carnitine (ALCAR) for the prevention of chemotherapy-induced peripheral neuropathy in patients with relapsed or refractory multiple myeloma treated with bortezomib, doxorubicin and low-dose dexamethasone: A study from the Wisconsin Oncology Network

Natalie Callander, Stephanie Markovina, Jens Eickhoff, Paul Hutson, Toby Campbell, Peiman Hematti, Ronald Go, Robert Hegeman, Walter Longo, Eliot Williams, Fotis Asimakopoulos, Shigeki Miyamoto

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Purpose: Retreatment with bortezomib (B) is often considered for patients with relapsed multiple myeloma (MM), but this strategy is hindered by uncertainty of response and emergence of B-induced peripheral neuropathy (PN). We incorporated acetyl-l-carnitine (ALCAR) to prevent PN and allow for adequate dosing. We also investigated the correlation between B-inducible NF-κB activation and response to therapy. Methods: Nineteen patients with relapsed/refractory MM received up to 8 cycles of intravenous bortezomib, doxorubicin and oral low-dose dexamethasone (BDD) to evaluate response and toxicity. Thirteen additional patients received prophylactic ALCAR (BDD-A). Patients receiving BDD-A were evaluated by FACT-GOG-TX, FACIT-Fatigue, Neuropathic Pain index (NPI) and Grooved Pegboard (GP) testing. Primary MM cells from 11 patients were tested for B-inducible NF-κB activation. Results: Seventy-six percent of subjects were refractory to previous treatment, 39 % refractory to bortezomib. Median cycles received were 5. CR + PR for the entire group were 53 % and did not differ between groups. Incidence of ≥3 PN was 32 % in the BDD group versus 15 % in the BDD-A group (p = ns). Patient-reported fatigue and PN measured by FACT-GOG-TX increased throughout the treatment period in the BDD-A group, although time to complete GP testing declined. In a sub-study examining constitutive bortezomib-inducible NF-κB activity in primary subject-specific MM cells, the presence of NF-κB activation correlated with lower likelihood of response. Conclusions: Addition of ALCAR to BDD did not alter the incidence or severity of PN in relapsed MM patients receiving a B-based regimen. Bortezomib-inducible NF-κB activation in patient-derived primary MM cells may be associated with poorer response.

Original languageEnglish (US)
Pages (from-to)875-882
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume74
Issue number4
DOIs
StatePublished - 2014
Externally publishedYes

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Acetylcarnitine
Oncology
Chemotherapy
Carnitine
Peripheral Nervous System Diseases
Multiple Myeloma
Refractory materials
Doxorubicin
Dexamethasone
Drug Therapy
Chemical activation
Fatigue
Fatigue of materials
Testing
Retreatment
7,7'-dimethoxy-(4,4'-bi-1,3-benzodioxole)-5,5'-dicarboxylic acid dimethyl ester
Bortezomib
Incidence
Neuralgia
Toxicity

Keywords

  • Acetyl-l-carnitine
  • Bortezomib
  • Multiple myeloma
  • Neuropathy
  • NF-kB

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Acetyl-l-carnitine (ALCAR) for the prevention of chemotherapy-induced peripheral neuropathy in patients with relapsed or refractory multiple myeloma treated with bortezomib, doxorubicin and low-dose dexamethasone : A study from the Wisconsin Oncology Network. / Callander, Natalie; Markovina, Stephanie; Eickhoff, Jens; Hutson, Paul; Campbell, Toby; Hematti, Peiman; Go, Ronald; Hegeman, Robert; Longo, Walter; Williams, Eliot; Asimakopoulos, Fotis; Miyamoto, Shigeki.

In: Cancer Chemotherapy and Pharmacology, Vol. 74, No. 4, 2014, p. 875-882.

Research output: Contribution to journalArticle

Callander, Natalie ; Markovina, Stephanie ; Eickhoff, Jens ; Hutson, Paul ; Campbell, Toby ; Hematti, Peiman ; Go, Ronald ; Hegeman, Robert ; Longo, Walter ; Williams, Eliot ; Asimakopoulos, Fotis ; Miyamoto, Shigeki. / Acetyl-l-carnitine (ALCAR) for the prevention of chemotherapy-induced peripheral neuropathy in patients with relapsed or refractory multiple myeloma treated with bortezomib, doxorubicin and low-dose dexamethasone : A study from the Wisconsin Oncology Network. In: Cancer Chemotherapy and Pharmacology. 2014 ; Vol. 74, No. 4. pp. 875-882.
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abstract = "Purpose: Retreatment with bortezomib (B) is often considered for patients with relapsed multiple myeloma (MM), but this strategy is hindered by uncertainty of response and emergence of B-induced peripheral neuropathy (PN). We incorporated acetyl-l-carnitine (ALCAR) to prevent PN and allow for adequate dosing. We also investigated the correlation between B-inducible NF-κB activation and response to therapy. Methods: Nineteen patients with relapsed/refractory MM received up to 8 cycles of intravenous bortezomib, doxorubicin and oral low-dose dexamethasone (BDD) to evaluate response and toxicity. Thirteen additional patients received prophylactic ALCAR (BDD-A). Patients receiving BDD-A were evaluated by FACT-GOG-TX, FACIT-Fatigue, Neuropathic Pain index (NPI) and Grooved Pegboard (GP) testing. Primary MM cells from 11 patients were tested for B-inducible NF-κB activation. Results: Seventy-six percent of subjects were refractory to previous treatment, 39 {\%} refractory to bortezomib. Median cycles received were 5. CR + PR for the entire group were 53 {\%} and did not differ between groups. Incidence of ≥3 PN was 32 {\%} in the BDD group versus 15 {\%} in the BDD-A group (p = ns). Patient-reported fatigue and PN measured by FACT-GOG-TX increased throughout the treatment period in the BDD-A group, although time to complete GP testing declined. In a sub-study examining constitutive bortezomib-inducible NF-κB activity in primary subject-specific MM cells, the presence of NF-κB activation correlated with lower likelihood of response. Conclusions: Addition of ALCAR to BDD did not alter the incidence or severity of PN in relapsed MM patients receiving a B-based regimen. Bortezomib-inducible NF-κB activation in patient-derived primary MM cells may be associated with poorer response.",
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T1 - Acetyl-l-carnitine (ALCAR) for the prevention of chemotherapy-induced peripheral neuropathy in patients with relapsed or refractory multiple myeloma treated with bortezomib, doxorubicin and low-dose dexamethasone

T2 - A study from the Wisconsin Oncology Network

AU - Callander, Natalie

AU - Markovina, Stephanie

AU - Eickhoff, Jens

AU - Hutson, Paul

AU - Campbell, Toby

AU - Hematti, Peiman

AU - Go, Ronald

AU - Hegeman, Robert

AU - Longo, Walter

AU - Williams, Eliot

AU - Asimakopoulos, Fotis

AU - Miyamoto, Shigeki

PY - 2014

Y1 - 2014

N2 - Purpose: Retreatment with bortezomib (B) is often considered for patients with relapsed multiple myeloma (MM), but this strategy is hindered by uncertainty of response and emergence of B-induced peripheral neuropathy (PN). We incorporated acetyl-l-carnitine (ALCAR) to prevent PN and allow for adequate dosing. We also investigated the correlation between B-inducible NF-κB activation and response to therapy. Methods: Nineteen patients with relapsed/refractory MM received up to 8 cycles of intravenous bortezomib, doxorubicin and oral low-dose dexamethasone (BDD) to evaluate response and toxicity. Thirteen additional patients received prophylactic ALCAR (BDD-A). Patients receiving BDD-A were evaluated by FACT-GOG-TX, FACIT-Fatigue, Neuropathic Pain index (NPI) and Grooved Pegboard (GP) testing. Primary MM cells from 11 patients were tested for B-inducible NF-κB activation. Results: Seventy-six percent of subjects were refractory to previous treatment, 39 % refractory to bortezomib. Median cycles received were 5. CR + PR for the entire group were 53 % and did not differ between groups. Incidence of ≥3 PN was 32 % in the BDD group versus 15 % in the BDD-A group (p = ns). Patient-reported fatigue and PN measured by FACT-GOG-TX increased throughout the treatment period in the BDD-A group, although time to complete GP testing declined. In a sub-study examining constitutive bortezomib-inducible NF-κB activity in primary subject-specific MM cells, the presence of NF-κB activation correlated with lower likelihood of response. Conclusions: Addition of ALCAR to BDD did not alter the incidence or severity of PN in relapsed MM patients receiving a B-based regimen. Bortezomib-inducible NF-κB activation in patient-derived primary MM cells may be associated with poorer response.

AB - Purpose: Retreatment with bortezomib (B) is often considered for patients with relapsed multiple myeloma (MM), but this strategy is hindered by uncertainty of response and emergence of B-induced peripheral neuropathy (PN). We incorporated acetyl-l-carnitine (ALCAR) to prevent PN and allow for adequate dosing. We also investigated the correlation between B-inducible NF-κB activation and response to therapy. Methods: Nineteen patients with relapsed/refractory MM received up to 8 cycles of intravenous bortezomib, doxorubicin and oral low-dose dexamethasone (BDD) to evaluate response and toxicity. Thirteen additional patients received prophylactic ALCAR (BDD-A). Patients receiving BDD-A were evaluated by FACT-GOG-TX, FACIT-Fatigue, Neuropathic Pain index (NPI) and Grooved Pegboard (GP) testing. Primary MM cells from 11 patients were tested for B-inducible NF-κB activation. Results: Seventy-six percent of subjects were refractory to previous treatment, 39 % refractory to bortezomib. Median cycles received were 5. CR + PR for the entire group were 53 % and did not differ between groups. Incidence of ≥3 PN was 32 % in the BDD group versus 15 % in the BDD-A group (p = ns). Patient-reported fatigue and PN measured by FACT-GOG-TX increased throughout the treatment period in the BDD-A group, although time to complete GP testing declined. In a sub-study examining constitutive bortezomib-inducible NF-κB activity in primary subject-specific MM cells, the presence of NF-κB activation correlated with lower likelihood of response. Conclusions: Addition of ALCAR to BDD did not alter the incidence or severity of PN in relapsed MM patients receiving a B-based regimen. Bortezomib-inducible NF-κB activation in patient-derived primary MM cells may be associated with poorer response.

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