Therapy-related myelodysplastic syndrome and acute myeloid leukemia in patients with chronic lymphocytic leukemia treated with fludarabine and cyclophosphamide

doi:10.1016/j.biopha.2011.04.006

Biomedicine & Pharmacotherapy

Volume 65, Issue 5, August 2011, Pages 319-321

https://doi.org/10.1016/j.biopha.2011.04.006 Get rights and content

Abstract

We retrospectively studied four cases of t-MDS/AML among 210 (1.9%) consecutive patients with CLL treated at a single center with fludarabine and cyclophosphamide (FC) either as the first- or second-line therapy. The median follow-up of the whole cohort of patients was 46 months (range: 7–60). Two of these patients (2/130, 1.7%) had been treated with FC only, and two more (2/80, 2.3%) with CHOP and CHOP + FND, respectively, prior to FC. The median age was 61.5 years (range: 49–71); three were male. They developed t-MDS/AML after a median latency period of 41 months (range: 7–56) from the FC completion. Chromosomal aberrations with an adverse prognostic impact were present in the karyotype of all four patients, including abnormalities of chromosome 5 in three of them, and a rare chromosomal translocation in one patient. Median survival after t-MDS/AML diagnosis was 4 months (range: 2–8). Although the agents administered prior to FC make it difficult to assess the risk of t-MDS/AML attributable to FC, this report might be a valuable addition to the literature.

Introduction

Fludarabine has been considered as the most effective agent in the treatment of chronic lymphocytic leukemia (CLL) either as a single agent or in fludarabine-based regimens. The toxicity profile of fludarabine encompasses prolonged myelosuppression and immunosuppression together with hematopoetic stem cell toxicity. These are potentiated in combination with DNA damaging agents [1]. These effects may contribute to the increased risk of therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) due to synergistic effects on the inhibition of DNA repair in fludarabine-based regimens [2], [3]. We retrospectively studied four patients with t-MDS/AML arising within a cohort of 210 patients with CLL treated at a single center with fludarabine in combination with cyclophosphamide (FC).

Section snippets

Patients and methods

From 2004 to 2009, 210 consecutive consenting patients were given FC either as the first-line (130; 62%) or as the second-line therapy (80; 38%) for CLL following the approval of the Institutional Review Board. FC was delivered as follows: fludarabine 25 mg/m² i.v. and cyclophosphamide 200 mg/m² i.v. for three consecutive days every 28 days. The median follow-up of the whole cohort of patients analyzed was 46 months (range: 7–60). WHO diagnostic criteria for t-MDS/AML [4] together with FAB criteria

Results

Four out of 210 (1.9%) CLL patients developed t-MDS/AML after a median follow-up of 41 months (range: 7–56) after completion of FC treatment. t-MDS/AML developed in 2/130 (1.5%) and 2/80 (2.5%) patients after completion of FC as the first- or second-line therapy, respectively. There was no difference in the incidences (P > 0.05). The patients’ characteristics are summarized in Table 1. The male/female (M:F) ratio was 3:1 and the median age was 61 years (range: 49–71). The characteristics of the

Discussion and conclusions

Fludarabine is widely used in the treatment of CLL, inducing high rates of durable remissions. It was not initially suspected as a risk factor for t-MDS/AML development [8], [9], [10], [11]. However, the combination of fludarabine with DNA damaging agents may increase the risk of t-MDS/AML [2], [3], [12], [13], [14] though accurate assessment of the true rate of t-MDS/AML following fludarabine is often difficult to make [15].

The rate of t-MDS/AML in the CALGB 9011 study of frontline CLL

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Sources of funding. This study was supported by the Ministry of Science and Technological Development of the Republic of Serbia, No. 41004.

Acknowledgements

Ana Ivkovic, Senior Librarian, Institute for Oncology and Radiology of Serbia deserves special mention for arranging for the relevant articles.

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Cited by (13)

Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY
2023, eClinicalMedicine
Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work.
We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022.
In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).
The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79–4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49–2.11; p < 0.001/OR = 1.89; 95% CI = 1.6–2.24; p < 0.001).
CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36–2.41; p < 0.001/OR = 2.11; 95% CI = 1.12–3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08–0.33; p < 0.001).
Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001).
OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS.
AbbVie, and EU/EFPIA Innovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026.
Significant current epidemiological trend: Haematological malignancies as subsequent primary tumours in cancer patients
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Citation Excerpt :
The differences in estimated SIR values might be caused by different time periods involved in the analyses, numbers of patients, duration of follow-up, and rules for the definition and classification of SPT. Our study revealed a significantly increased risk of development of a subsequent HM after chronic leukaemias (CLL, CML), which is in accordance with published studies [15,45–52]. Kumar et al. (2019) demonstrated that among subsequent HM after CLL, most of the excess risk was contributed by NHL and by HL, which corresponds to our results.
Numbers of patients who develop subsequent primary tumours have markedly increased recently. This study aimed to carry out a comprehensive analysis documenting the risk of incidence of subsequent haematological malignancies.
The Czech National Cancer Registry was the main data source, containing records of 126,822 haematological malignancies diagnosed in the period 1977–2016. Subsequent haematological malignancies were identified according to IACR rules. Joinpoint regression was employed to assess the time trends. The risk of development of subsequent haematological malignancy was evaluated by the standardised incidence ratio. The Kaplan–Meier curves were used to assess the differences in survival.
Age-standardised incidence of subsequent haematological malignancies increased from 0.5 in 1977 to 9.1 in 2016. In 1992, there was a significant change in the trend: a sharp increase by 7.7 % annually was revealed thereafter. The risk of development of a haematological malignancy was approximately 1.5 times higher in persons with history of any cancer than in the general Czech population. Patients with haematological malignancies – mainly myelodysplastic syndromes, polycythaemia vera and non-Hodgkin lymphoma – were shown to be at the highest risk of developing a subsequent haematological malignancy. While the median survival following a first haematological malignancy was 2.3 years, it was only 1.1 years for subsequent haematological malignancies (p < 0.001).
Our study identified the highest-risk diagnoses in terms of development of subsequent haematological malignancy. The results might be useful to set up correctly follow-up procedures from which cancer patients could benefit.
Myeloid neoplasms in the setting of chronic lymphocytic leukaemia/chronic lymphocytic leukaemia-like disease: a clinicopathological study of 66 cases comparing cases with prior history of treatment to those without
2022, Journal of Clinical Pathology
Concurrent Onset of Chronic Lymphocytic Leukemia and Atypical Phenotype Acute Myeloid Leukemia Revealed by Autopsy
2021, Case Reports in Oncology
Trends in the risk of second primary malignancies among survivors of chronic lymphocytic leukemia
2019, Blood Cancer Journal
Significant impact of immunosuppression on the incidence of secondary malignancies following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with indolent B-cell neoplasms
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Original articleTherapy-related myelodysplastic syndrome and acute myeloid leukemia in patients with chronic lymphocytic leukemia treated with fludarabine and cyclophosphamide

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion and conclusions

Disclosure of interest

Acknowledgements

Cancer Genet Cytogenet

Blood

Blood

Blood

Blood

Blood

Blood

Blood

DNA repair initiated in chronic lymphocytic leukemia lymphocytes by 4-hydroperoxycyclophosphamide is inhibited by fludarabine and clofarabine

Clin Can Res

Treatment-related myelodysplasia following fludarabine combination chemotherapy

Haematologica

Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil. Results of an intergroup study, cancer and leukemia group B9011

J Clin Oncol

Original article
Therapy-related myelodysplastic syndrome and acute myeloid leukemia in patients with chronic lymphocytic leukemia treated with fludarabine and cyclophosphamide