Case Report
Influence of Haemodialysis on Imatinib Plasma Levels in a Case of Philadelphia Positive Acute Lymphoblastic Leukemia
Diego de Goycoechea1, Eberhard Schleyer2, Olaia Naveiras1, Norbert Gattermann3 and Sabine Blum1*
1Service of Hematology, Centre Hospitalier Universitaire Vaudois, Switzerland
2Carl Gustav Carus University, Internal Medicine I, Division Hematology and Oncology, Germany
3Department of Hematology, Oncology, and Clinical Immunology, Germany
*Corresponding author: Dr. Sabine Blum, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland
Published: 25 May, 2018
Cite this article as: de Goycoechea D, Schleyer E,
Naveiras O, Gattermann N, Blum
S. Influence of Haemodialysis on
Imatinib Plasma Levels in a Case
of Philadelphia Positive Acute
Lymphoblastic Leukemia. Ann Clin
Case Rep. 2018; 3: 1512.
Background
Imatinib is a commonly used drug for the treatment of chronic myeloid leukemia (CML),
acute lymphoblastic leukemia (ALL) with presence of a Philadelphia chromosome (Ph+), and
gastrointestinal stromal tumors (GIST). Thanks to the availability of tyrosine kinase inhibitors
(TKI) including Imatinib, the standard treatment of these pathologies has changed significantly
and their outcome has vastly improved. The introduction of Imatinib two decades ago constituted
a revolution in the treatment of CML, both because it was the first molecularly targeted therapy
in oncology and because it has allowed the field to move away from aggressive first-line therapies,
including hematopoietic stem cell transplantation. The main circulating active metabolite of Imatinib
in humans is the N-demethylated piperazine derivative CGP74588, also known as N-desmethyl-STI
(Des-M-STI) and formed predominantly by CYP3A4. Whilst there are many studies looking at TKI
usage, very little is known about the elimination and thus the safe dosage of Imatinib and its main
active metabolite CGP74588 in patients receiving hemodialysis. This data is critical to predict both
safety and efficacy in such clinical settings.
Imatinib is known to be primarily excreted in the faeces, with 68% eliminated from the body by
this route, and only 3% to a maximum of 13% being excreted by the kidneys [1,2]. Theoretically, the
potential for the drug to accumulate to toxic levels in patients with renal failure would be considered
to be low. However, the ability of hemodialysis to remove Imatinib and CGP74588 from the blood
has not been extensively investigated. Only rare individual case reports have been published,
mainly in the context of GIST, with one single CML case described [3-6]. All published cases in the
hemodialysis setting describe treatment with 400 mg of Imatinib as a single daily dose. To the best
of our knowledge, no case has been described as yet for the use of Imatinib in the context of acute
lymphoblastic leukemia (ALL) in a hemodialysis setting. Moreover, our patient received a daily dose
of 600 mg/d rather than the usual dose dose of 400 mg/d because higher doses are recommended
for ALL treatment.
We would like to share our experience of dosing Imatinib in an ALL patient receiving 600 mg/d
while undergoing hemodialysis treatment.
Case Presentation
A 62-year-old man was diagnosed with Philadelphia positive, bcr-abl positive (p190) ALL.
Chemotherapy was commenced according to the German Multicenter ALL protocol (GMALL),
which included Imatinib 600 mg daily. During this treatment, the patient developed neutropenic
sepsis with paralytic ileus, which resulted in end-stage kidney failure requiring hemodialysis.
Imatinib was continued at 600 mg/d, and serial measurements of both Imatinib and CGP74588 were
taken for three consecutive days, from plasma as well as from the dialysate. The patient died from
paralytic ileus shortly after having started dialysis treatment. For a detailed list of measurements of
Imatinib and CGP74588 in plasma and dialysate, see Table 1.
Results showed that only 0.005% of the Imatinib dose was removed during hemodialysis,
demonstrating poor efficacy of hemodialysis in eliminating the drug in our clinical setting.
Noteworthy, the plasma levels of both Imatinib and its main metabolite CGP74588 were found to be approximately three times lower than predicted. It is unclear whether
this was secondary to reduced intestinal absorption due to ileus, or to
an unusual volume of distribution.
Table 1
Discussion and Conclusion
Despite the fact that Imatinib constitutes the gold standard
for the treatment of CML as well as GIST, data on Imatinib use in
patients undergoing hemodialysis is sparse, with only a few GIST
cases and one CML case described. Most of these case reports simply
describe the feasibility, the efficacy against the malignancy, and the
lack of major side effects of the Imatinib treatment in the context
of hemodialysis [3]. Niikura and colleagues describe a 75-year-old
male patient suffering from GIST with multiple metastases, achieving
stable disease upon 400 mg of Imatinib daily, without major side
effects. Wada et al. published the case of a 69-year-old male patient
with GIST achieving a partial response without major side effects,
also with daily treatment of 400 mg Imatinib. Ozdemir and colleagues
published a 54-year-old female patient suffering from CML who
showed an excellent response, with achievement of molecular and
cytogenetic remission following 3 months of treatment with 400mg
of Imatinib daily; no significant side effects occurred during followup
[4].
Pappas et al. analyzed serial blood samples taken from a
patient with GIST and metastasis to the liver, who was undergoing
hemodialysis and was treated with Imatinib 400 mg/day [5].
Results were comparable to control samples taken from patients
receiving the same treatment, but with normal renal function. The
authors concluded that standard doses of 400 mg/day may be safely
maintained in patients undergoing hemodialysis.
Regarding other TKIs, one paper on the feasibility of Nilotinib
treatment in the hemodialysis setting has been published to date, with
3 cases suffering from CML [6]. Pharmacokinetics in all three patients
showed no significant difference between the plasma concentrations
of Nilotinib before and after dialysis, demonstrating that, just like
Imatinib, Nilotinib is not cleared by hemodialysis and that treatment
is feasible and effective.
Further pharmacological data on the use of TKIs in the dialysis
setting is lacking. However, with a rising prevalence of CML
patients receiving long-term treatment with Imatinib or other TKIs,
the prevalence of such patients undergoing hemodialysis is also
expected to rise, even though this is not reflected in recent studies or
publications. Typically, this patient group is excluded from clinical
trials of Imatinib and other TKIs.
As yet, no data has been published on Imatinib treatment in
patients with Ph+ ALL undergoing hemodialysis, even though TKIs
are now regularly used in combination with chemotherapy in such
patients [7]. While second generation TKIs are now preferred for
the treatment of Ph+ ALL, our data is still relevant for hemodialysis
patients receiving treatment with Imatinib, regardless of the
underlying malignancy.
Our patient died due to paralytic ileus shortly after starting
hemodialysis therapy. Nevertheless, the measurements of Imatinib
and CGP74599 that we conducted in plasma and dialysate suggest
that Imatinib at a dose of 600 mg/d can be safely employed in patients
undergoing hemodialysis. Very little of the substance was found in
the dialysate, indicating that Imatinib is hardly eliminated by this
route. More work is needed to determine the optimal safe dose of
Imatinib in patients on hemodialysis.
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