Clinical and experimental Medicine
Contributions
Type: Publication Only
Background
The Swedish group reported that 30% of patients who stopped imatinib presented by the first 2 months musculoskeletal pains, localized to shoulders and hips or extremities, like a rheumatic polymyalgia (Richter J, JCO 32: 25 -2014). Some of these cases have been described as sensitive to paracetamol, whereas other patients need long-term treatment with corticosteroids.
Aims
The aim of this study was the strict molecular and clinical follow-up of patients who stopped imatinib for intolerance in order to do a precocious diagnosis and start an appropriate treatment for this “withdrawal syndrome”.
Methods
Seven patients discontinued imatinib in 2014 at the Hematology Unit of the Pisa University; median age was 70 years (range 54-75); all patients received imatinib for more than 3 years, with a median time from diagnosis of 10 years.
Initial Sokal risk score was low in 4 patients, intermediate in 2, and high in one patient; EUTOS score was low in all cases, except for one. All patients were in deep molecular response (at least MR4.5) from a minimum of 24 months at the moment of discontinuation.
Treatment was interrupted because of non-hematological toxicities (PAOD, bleeding, alopecia, eyes, liver, skin toxicity). BCR-ABL1/ABL1 IS ratio was monitored by quantitative PCR every month.
Reactive C protein, interleukin-2, interleukin-10, TNFa, PDGFb, VEGF, and interferong were measured in the plasma by ELISA.
Results
Two of our 7 patients developed the “withdrawal syndrome” after 2 and 3 weeks from the imatinib discontinuation, respectively. They presented muscolo-skeletal pains, localized to shoulders, arms and hip; these symptoms were graded as 2.
The C-reactive protein serum level was normal in one case and only slightly increased in the other one; lactate dehydrogenase and protein electhrophoresis were normal in both cases.
None of the 7 patients lost the deep molecular response during the follow-up (median 6 months, range 3-11 months).
Interleukin-2, interleukin-10, TNFa, IFNg, and VEGF were in the normal range; interestingly, in both patients presenting the “withdrawal syndrome” PDGFRb resulted increased (2.5 fold higher than the highest value in the normal range).
Both these patients did not respond to paracetamol 1g trice/day, thus corticosteroids were given (16 mg methyl-prednisolone per day), with tapering within 8 weeks up to 4 mg. Both patients showed a clear improvement within days; after 8 weeks steroid was discontinued, but symptoms, even if milder, reappeared. Both patients still receive 4 mg/day. PDGFb in this phase was still high, even if significantly reduced in respect of the onset of the syndrome.
Summary
Our study confirms, even if in a limited experience, the feasibility of the TKI discontinuation, but also the presence of the “withdrawal syndrome”. It is well known that imatinib inhibits PDGFRb; PDGFRb has been also reported to contribute to synovitis by re-directing synovial fibroblasts toward a more aggressive phenotype (Rosengren S, 2010), and increased expression of PDGFb was also detected in the inflamed synovia, supporting its relevant role in the inflammatory processes (Reuterdhal C, 1991).
Consequently, we could hypothesize that the discontinuation of imatinib, stopping the PDGFRb inhibition, could activate the PDGF-mediated arthalgias.
Keyword(s): Chronic myeloid leukemia, Imatinib, PDGFRB
Session topic: Publication Only
Type: Publication Only
Background
The Swedish group reported that 30% of patients who stopped imatinib presented by the first 2 months musculoskeletal pains, localized to shoulders and hips or extremities, like a rheumatic polymyalgia (Richter J, JCO 32: 25 -2014). Some of these cases have been described as sensitive to paracetamol, whereas other patients need long-term treatment with corticosteroids.
Aims
The aim of this study was the strict molecular and clinical follow-up of patients who stopped imatinib for intolerance in order to do a precocious diagnosis and start an appropriate treatment for this “withdrawal syndrome”.
Methods
Seven patients discontinued imatinib in 2014 at the Hematology Unit of the Pisa University; median age was 70 years (range 54-75); all patients received imatinib for more than 3 years, with a median time from diagnosis of 10 years.
Initial Sokal risk score was low in 4 patients, intermediate in 2, and high in one patient; EUTOS score was low in all cases, except for one. All patients were in deep molecular response (at least MR4.5) from a minimum of 24 months at the moment of discontinuation.
Treatment was interrupted because of non-hematological toxicities (PAOD, bleeding, alopecia, eyes, liver, skin toxicity). BCR-ABL1/ABL1 IS ratio was monitored by quantitative PCR every month.
Reactive C protein, interleukin-2, interleukin-10, TNFa, PDGFb, VEGF, and interferong were measured in the plasma by ELISA.
Results
Two of our 7 patients developed the “withdrawal syndrome” after 2 and 3 weeks from the imatinib discontinuation, respectively. They presented muscolo-skeletal pains, localized to shoulders, arms and hip; these symptoms were graded as 2.
The C-reactive protein serum level was normal in one case and only slightly increased in the other one; lactate dehydrogenase and protein electhrophoresis were normal in both cases.
None of the 7 patients lost the deep molecular response during the follow-up (median 6 months, range 3-11 months).
Interleukin-2, interleukin-10, TNFa, IFNg, and VEGF were in the normal range; interestingly, in both patients presenting the “withdrawal syndrome” PDGFRb resulted increased (2.5 fold higher than the highest value in the normal range).
Both these patients did not respond to paracetamol 1g trice/day, thus corticosteroids were given (16 mg methyl-prednisolone per day), with tapering within 8 weeks up to 4 mg. Both patients showed a clear improvement within days; after 8 weeks steroid was discontinued, but symptoms, even if milder, reappeared. Both patients still receive 4 mg/day. PDGFb in this phase was still high, even if significantly reduced in respect of the onset of the syndrome.
Summary
Our study confirms, even if in a limited experience, the feasibility of the TKI discontinuation, but also the presence of the “withdrawal syndrome”. It is well known that imatinib inhibits PDGFRb; PDGFRb has been also reported to contribute to synovitis by re-directing synovial fibroblasts toward a more aggressive phenotype (Rosengren S, 2010), and increased expression of PDGFb was also detected in the inflamed synovia, supporting its relevant role in the inflammatory processes (Reuterdhal C, 1991).
Consequently, we could hypothesize that the discontinuation of imatinib, stopping the PDGFRb inhibition, could activate the PDGF-mediated arthalgias.
Keyword(s): Chronic myeloid leukemia, Imatinib, PDGFRB
Session topic: Publication Only