The Egyptian Journal of Haematology

CASE REPORT
Year
: 2015  |  Volume : 40  |  Issue : 2  |  Page : 104--106

Fludarabine and bradycardia in recipients of allogeneic stem cell transplant: a case series


Chepsy C Philip 
 Department of Clinical Haematology, Christian Medical College, Ludhiana, Punjab, India

Correspondence Address:
Chepsy C Philip
Department of Clinical Haematology, Christian Medical College, Ludhiana - 141 008, Punjab
India

Abstract

Fludarabine is being increasingly used both as a chemoimmunotherapeutic agent and in conditioning regimens for stem cell transplant. ECG disturbances with this increasingly used drug have never been reported. This report describes a patient who developed bradycardia following fludarabine administration, prompting an assessment for rhythm irregularities in subsequent patients undergoing stem cell transplant using a fludarabine-based conditioning regimen. In a series of 10 patients who received fludarabine as part of their conditioning, there was a significant effect on QTc interval (mean difference 30.6 ms; P = 0.002) and heart rate (mean difference −18.9 beats/min; P = 0.003). In conclusion, caregivers need to be alert to recognize the potential for unrecognized adverse events even in frequently used drugs. Fludarabine has a potential for rhythm disturbances.



How to cite this article:
Philip CC. Fludarabine and bradycardia in recipients of allogeneic stem cell transplant: a case series.Egypt J Haematol 2015;40:104-106


How to cite this URL:
Philip CC. Fludarabine and bradycardia in recipients of allogeneic stem cell transplant: a case series. Egypt J Haematol [serial online] 2015 [cited 2021 Sep 21 ];40:104-106
Available from: http://www.ehj.eg.net/text.asp?2015/40/2/104/161297


Full Text

 Introduction



Fludarabine, a nucleoside analogue, is an important chemoimmunotherapeutic agent in the treatment of haematologic disorders [1],[2] . Recent increase in the use of the reduced intensity conditioning regimens have further fuelled its use [3] . Cardiovascular toxicities are reported mainly in the context of anthracyclines [4] . ECG disturbances have not been previously reported with this agent. We recently noted ECG abnormalities in a patient receiving this agent. The index case was a 43-year-old man with myelodysplastic syndrome, who was undergoing transplant with a fludarabine/melphalan-conditioning regime. On routine monitoring it was noticed that following fludarabine infusion he developed bradycardia. He was asymptomatic and his baseline ECG and echocardiography performed before transplant had been normal. It was observed that the bradycardia resolved spontaneously. A causal association to fludarabine was postulated, and subsequent patients admitted to the transplant unit on a fludarabine-based regimen were serially monitored with ECG. A few developed transient asymptomatic bradycardia, which was detected on routine ECG monitoring. Considering the increased usage of fludarabine, it is important for service providers to recognize this ECG phenomenon. We report our findings from a series of 10 patients who received fludarabine as part of their conditioning for transplant.

 Materials and methods



The ECGs of 10 consecutive patients admitted to the transplant unit receiving a fludarabine-based conditioning were analysed following infusion. All patients had a normal baseline ECG and echocardiography before fludarabine administration. Patients recorded to have bradycardia were monitored for worsening. No disturbance persisted beyond an hour. Fludarabine infusions were administered over an hour as per protocol. Chemotherapy consent was obtained as per protocol, and no further consent was sought. Fludarabine was used as part of the preassigned conditioning protocol based on the transplant indication for the patient - namely, Treo-Flu-T in thalassaemia, Flu-Cy in aplastic anaemia and Flu-Mel in acute myeloid leukaemia/myelodysplastic syndrome. A sample t-test was used for statistical analysis of the hypothesis using Predictive Analytics Software-20 (International Business Machines, SPSS, Chicago, IL, USA).

 Results



In the series of 10 patients admitted to the allogenic stem cell transplant unit using fludarabine as part of their conditioning regimen, we observed a significant association of fludarabine administration with QTc interval (mean difference 30.6 ms; P=0.002) and heart rate (mean difference −18.9 beats/min; P=0.003) ([Table 1]). The PR interval showed a mean difference of −18.2 ms, which was not statistically significant.{Table 1}

 Discussion



Fludarabine, a cancer chemotherapeutic agent, mediates its cytotoxicity by the termination of mRNA transcription, with consequent depletion of critical proteins essential for cell survival, activation of the apoptosome pathway and inhibition of DNA repair [5],[6] . It is a nucleoside pro-drug, which is converted to the free nucleoside 9-β-d-arabinosyl-2-fluoroadenine (F-Ara-A), entering cells and accumulating as the 5¢-triphosphate, F-Ara-ATP [7] . With reduced intensity conditioning being suggested as a desirable therapeutic modality for the treatment of patients with malignant and nonmalignant indications complemented by the better tolerability of fludarabine, its use in stem cell transplants is on the rise [8],[9],[10] .

Previously, fludarabine as a cause of bradycardia had been speculated in a patient with refractory leukaemia [11] . The results and hypothesis suggest that this is not an infrequent phenomenon and needs to be recognized.

One can hypothesize that the purine analogue fludarabine and more possibly its intermediate fluoroadenosine might have electrophysiologic effects similar to adenosine. Adenosine serves as a signalling molecule and mediates its effect on arrhythmias by shortening of action potential duration in atrial myocytes mediated by the potassium current, a shortening of action potential duration and hyperpolarization in sinus node cells with antiadrenergic electrophysiological effects resulting from inhibition of adenylyl cyclase [12],[13] . Although none of the patients had developed any further rhythm disturbance, the association of adenosine with rhythm disturbances should alert caregivers to monitor appropriately [14] . Recognition of this ECG phenomenon might limit extensive evaluation.

Study limitations

Many patients who undergo transplant have been exposed to multiple chemotherapeutic agents with potential cardiotoxicity. This might serve as likely confounders to the effect observed in this report.A comparison of the ECG values before and after fludarabine administrarion would possibly have been more informative.In addition, serum levels of the prodrug or the intermediates were not measured, and we have inferred from medical literature to postulate a hypothesis.

Animal models would serve as better evidence for a hypothesis. Moreover, a continuous holter monitoring might highlight the magnitude of changes better. A well-designed protocol with strict inclusion and exclusion criteria might help in validating this observation.

 Conclusion



This report describes an ECG phenomenon with the use of fludarabine. This phenomenon does not appear to be related to electrolyte disturbances. Caregivers need to recognize the potential for this phenomenon.

 Acknowledgements



The author thanks Sister Reena and the Transplant unit staff at CMC vellore.

Conflicts of interest

There are no conflicts of interest.

References

1Ysebaert L, Gross E, Kuhlein E, Blanc A, Corre J, Fournié JJ, et al. Immune recovery after fludarabine-cyclophosphamide-rituximab treatment in B-chronic lymphocytic leukemia: implication for maintenance immunotherapy. Leukemia 2010; 24 :1310-1316.
2 Shvidel L, Cohn M, Sigler E. Pharmacotherapy update: fludarabine in the treatment of non-Hodgkin lymphoma. Clinical Medicine: Therapeutics 2009; 1 :359-377.
3 Slack JL, Dueck AC, Fauble VD, Sproat LO, Reeder CB, Noel P, et al. Reduced toxicity conditioning and allogeneic stem cell transplantation in adults using fludarabine, carmustine, melphalan, and antithymocyte globulin: outcomes depend on disease risk index but not age, comorbidity score, donor type, or human leukocyte antigen mismatch. Biol Blood Marrow Transplant 19 :1167-1174.
4Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT, et al. ESMO Guidelines Working Group Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012; 23 :vii155-vii166.
5 Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues: mechanisms of drug resistance and reversal strategies. Leukemia 2001; 15 :875-890.
6 Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol 2002; 3 :415-424.
7 Gandhi V, Plunkett W. Cellular and clinical pharmacology of fludarabine. Clin Pharmacokinet 2002; 41 :93-103.
8 Kang HJ, Shin HY, Park JE, Chung NG, Cho B, Kim HK, et al.Korean Society of Pediatric Hematology-Oncology Successful engraftment with fludarabine, cyclophosphamide, and thymoglobulin conditioning regimen in unrelated transplantation for severe aplastic anemia: a phase II prospective multicenter study. Biol Blood Marrow Transplant 2010; 16 :1582-1588.
9 George B, Mathews V, Viswabandya A, Srivastava A, Chandy M. Fludarabine-based reduced intensity conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with aplastic anemia and fungal infections. Clin Transplant 2009; 23 :228-232.
10Bitan M, Or R, Shapira MY, Aker M, Resnick IB, Ackerstein A, et al. Fludarabine-based reduced intensity conditioning for stem cell transplantation of Fanconi anemia patients from fully matched related and unrelated donors. Biol Blood Marrow Transplant 2006; 12 :712-718.
11Chung-Lo W, Hsieh CY, Chiu CF, Bai LY. Fludarabine-induced bradycardia in a patient with refractory leukemia. Hematol Oncol Stem Cell Ther 2010; 3 :99-100.
12Eltzschig HK. Adenosine: an old drug newly discovered. Anesthesiology 2009; 111 :904-915.
13Engelstein ED, Lippman N, Stein KM, Lerman BB. Mechanism: specific effects of adenosine on atrial tachycardia. Circulation 1994; 89 :2645-2654.
14Mallet ML. Proarrhythmic effects of adenosine: a review of the literature. Emerg Med J 2004; 21:408-410.