Treatment-related acute myeloid leukemia in a chronic lymphocytic leukemia patient: role of fludarabine?

Introduction

Chronic lymphocytic leukemia (CLL) is associated with a two-fold increased risk of developing a second malignant tumor, most commonly a skin cancer [Travis et al. 1992; Velez et al. 2014]. CLL is also known to be associated with an increased frequency of second hematological malignancies [Hatoum et al. 2007]. In majority of cases, this usually involves a disease transformation to an aggressive non-Hodgkin lymphoma, multiple myeloma or prolymphocytic lymphoma [Bracey et al. 1989]. CLL patients can rarely develop acute myeloid leukemia (AML) [Bracey et al. 1989]. Similarly patients with myeloproliferative diseases are also at increased risk of developing lymphoid malignancies [Frederiksen et al. 2011]. This suggests that myeloid malignancies can transform to lymphoid malignancies and vice versa. In the majority of cases, AML is diagnosed after the therapy of CLL. In addition, rare cases of AML and CLL have been diagnosed simultaneously in previously untreated patients [Molero et al. 2001; Park et al. 2009]. In this report, we present a case of a woman with a history of previously treated CLL, who developed AML.

Case description

A 78-year-old woman was referred to our institution for acute-onset of fever, dyspnea, epigastric discomfort, one episode of coffee-ground emesis and multiple skin bruises. Past medical history was significant for Rai stage I CLL diagnosed 6 years ago based on incidental finding of leukocytosis with circulating absolute lymphocyte count of 7600 µ/l. A peripheral blood flow cytometry demonstrated a mature CD5 and CD23 positive B-cell population expressing CD19, low-density CD 20, CD24, CD25 and intermediate density, monotypic lambda light chains at 74% of lymphocytes, consistent with CLL. She continued to do well on active surveillance. On disease progression, approximately 4 years later, she underwent a bone marrow biopsy, which confirmed the diagnosis. Cytogenetics on bone marrow biopsy showed 46,XX[20], whereas fluorescence in situ hybridization (FISH) for CLL panel demonstrated deletion of 13q14 (17%) but was negative for a rearrangement of the IgH region at 14q32, trisomy 12 and deletions of 11q22.3, 13q34 and 17p13.1. The patient was treated with six cycles of fludarabine and rituximab. At the time of second disease progression, she underwent a biopsy of right cervical lymph node, which again confirmed CLL/small lymphocytic lymphoma without any histologic transformation to high-grade lymphoma. She was treated with six cycles of bendamustine and rituximab 6 months prior to the presentation.

Examination revealed multiple ecchymoses involving bilateral upper extremities and both thighs. There were no palpable peripheral lymph nodes or hepatosplenomegaly. Laboratory evaluation revealed a white blood count of 116,900 µ/l, hemoglobin of 10.1 gm/dl, platelet count of 45,000 µ/l, prothrombin time of 30 seconds, partial thromboplastin time of 55 seconds, fibrinogen of <60 mg/dl, and d-dimer of >4 µg/ml (normal 0.2–0.4 µg/ml). The coagulation profile was consistent with disseminated intravascular coagulation (DIC). Computed tomography scan of chest, abdomen and pelvis showed stable mediastinal, hilar, periesophageal, and retrocrural lymphadenopathy. Peripheral blood smear revealed circulating blasts (84%) and occasional schistocytes. A bone marrow biopsy revealed markedly hypercellular bone marrow (80%) with 95% blasts and promonocytes. Blasts were positive for nonspecific esterase and myeloperoxidase, and negative for Sudan black and specific esterase. Flow cytometry demonstrated a small residual CLL cell population present at 3.6% of lymphocytes. Cytogenetics and FISH revealed 46, XX, t(10;19)(q22;q13.1). FISH was negative for trisomy 12, deletions of 6q23, 11q22.3, 13q14, 13q34 and 17p13.1 and negative for a rearrangement of the IGH region at 14q32, including a t (11;14)(q13;q32). Additional studies were negative for trisomy 8 and negative for a rearrangement of the MLL (11q23) locus.

A diagnosis of treatment-related acute monoblastic leukemia (AML-M5) and persistent CLL was made. In addition to the supportive care including transfusion of fresh frozen plasma, cryoprecipitate and platelet for DIC, the patient received leukapheresis and hydroxyurea followed by chemotherapy with decitabine. She was subsequently discharged to a skilled nursing facility for continuation of further cycles of decitabine as an outpatient. Unfortunately, she passed away at the nursing facility approximately 2 weeks after the discharge.

Discussion

The rarity of development of AML in CLL patients prohibits clear understanding of the pathogenesis. We have reviewed existing literature and prior published cases (Table 1). The occurrence of therapy-related myelodysplastic syndrome (MDS) or AML in patients with CLL appears to be rare with one study reporting an incidence of <1% [Morrison et al. 2002]. In most of the reported cases, AML often occurs after treatment of CLL with chemotherapy and/or radiotherapy [Meloni et al. 2000; Park et al. 2009].

Table 1.

Published reports of chronic lymphocytic leukemia transforming into acute myeloid leukemia.

Study	Age/sex	CLL therapy	Latent period between CLL and AML	Karyotype	AML therapy	Outcome (from the time of AML diagnosis)
Meloni et al. [2000]	59/M	Fludarabine, then high-dose chemotherapy and autologous stem- cell transplant	~2 years	Trisomy 13	FLAG regimen (fludarabine, cytarabine and G-CSF)	Dead after 1+ month in remission from AML due to cardiorespiratory failure, likely from disseminated lung cancer
Park et al. [2009]	54/M	Fludarabine, cyclophosphamide, rituximab	2 years	Complex karyotype	Unclear	8+ month survival
Lam et al. [2005]	70/M	Fludarabine	8 years	46, XY, +1, der(1;7) (q10;p10)/46,XY	Palliative care	Referred to hospice care
Hatoum et al. [2007]	66/M	Fludarabine, cyclophosphamide	4 years	Normal	Idarubicin/ cytarabine	Remained in remission at 14 months follow up
Molero et al. [2001]	69/M	Untreated (had radiotherapy for concomitant prostate cancer)	4 year	t(15;17)	Idarubicin and all trans retinoic acid	Remained in remission at 1 year follow up
Mateu et al. [1997]	59/M	Received therapy for concurrent AML	Concurrent	Complex karyotype	Idarubicin, etoposide, cytarabine. mitoxantrone	Died of relapsed AML 6 months after diagnosis.
Lu et al. [2006]	59/M	Received therapy for concurrent AML	Concurrent	Inv(16)(p13.1q22), CBFβ-MYH11 fusion transcripts	Daunorubicin and cytarabine	Complete remission at 1-year follow up
Bracey et al. [1989]	72/M	Cyclophosphamide, vincristine, prednisone	2 weeks	Not mentioned	Decadron, adriamycin, vincristine, cytarabine	Patient died due to sepsis shortly after starting chemotherapy for AML
Robertson et al. [1994] (7 cases)	Median age 67 (range 59-76 years) 5 males 2 females	3 had no prior therapy, others had various traditional chemotherapy	Median 22 (range 0–156 months)	Various including complex karyotypes, abnormalities of chromosomes 5 and 7 as well as normal karyotype	Various mainly cytarabine-based therapy	6 died, one alive; Median survival 7 months (range 2-37 months)

AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; F, female; G-CSF, granulocyte colony-stimulating factor; M, Male.

The pathogenesis of these secondary malignancies may involve direct oncogenic effects of chemotherapy and radiation as well as decreased immune surveillance [Lam et al. 2005]. Therapy-related AML may occur following exposure to alkylating agents (chlorambucil, busulfan, melphalan), nitrosureas and topoisomerase-II inhibitors. A review of 1374 patients with CLL at MD Anderson Cancer Center found only three cases of AML/MDS at a median follow up of over 7 years; 72% of these patients had received therapy with an alkylating agent [Robertson et al. 1994]. Similarly, the incidence of therapy-related AML was 4.7% among 63 patients with advanced CLL treated at Memorial Sloan-Kettering Cancer Center treated with M-2 protocol, which included vincristine, carmustine and cyclophosphamide [Kempin et al. 1982].

The risk of secondary malignancies in patients treated with nucleoside analogs such as fludarabine and cladribine was previously debated. These drugs are potent immunosuppressants, which theoretically puts patients at risk of a second malignancy [Cheson et al. 1999]. Previous studies have failed to demonstrate an increased risk of hematological malignancy in patients treated with fludarabine or cladribine [Cheson et al. 1999; Robak et al. 2004]. More recent literature, however, has pointed out that fludarabine may be associated with higher risks of MDS and AML [Tam et al. 2006; Waterman et al. 2012]. Waterman and colleagues showed that the risk may be higher in patients receiving higher doses of fludarabine [Waterman et al. 2012]. Tam and colleagues suggested that combination therapy of fludarabine with other deoxyribonucleic acid damaging agents such as cyclophosphamide or mitoxantrone may increase the risks of MDS/AML [Tam et al. 2006]. Our patient had received fludarabine and an alkylating agent (bendamustine), however, AML developed relatively shortly after the completion of therapy with bendamustine. Hence, it is possible that fludarabine [Tam et al. 2006; Waterman et al. 2012] and less likely bendamustine [Cheson et al. 2010] may have contributed to the occurrence of a second malignancy. Many of the prior cases of treatment-related AML developing in the setting of CLL have also received fludarabine with [Hatoum et al. 2007; Park et al. 2009; Meloni et al. 2000; Robertson et al. 1994] or without [Lam et al. 2005] other leukemogenic therapies. Although this may just be related to the common use of fludarabine-based therapy in CLL, taken together with prior literature [Tam et al. 2006; Waterman et al. 2012], this may indicate a possible role of fludarabine in contributing to leukemogenesis.

Most reported cases of therapy-related AML appear to be of M0, M1, M2 and occasionally M4 subtype [Hatoum et al. 2007]. Therapy-related acute monoblastic leukemia (M5) in CLL, as in the present case, has rarely been reported [Lavabre-Bertrand et al. 1989]. Our review of previously published cases demonstrates that AML and CLL may be diagnosed concurrently or after a variable latency period (<2–13 years) [Bracey et al. 1989; Robertson et al. 1994; Mateu et al. 1997; Meloni et al. 2000; Molero et al. 2001; Lam et al. 2005; Lu et al. 2006; Hatoum et al. 2007; Park et al. 2009]. Rarely, the development of AML may not manifest with peripheral circulating blasts [Robertson et al. 1994]. Such diagnoses of coexisting aleukemic AML may be delayed if CLL is diagnosed solely based on a peripheral blood flow cytometry. Delayed diagnosis is also possible if the development of anemia and thrombocytopenia is interpreted as disease progression in a CLL patient with aleukemic AML, and a bone marrow biopsy is deferred.

Poor cytogenetics such as complex karyotype or deletion of 5 or 7 are frequently present in AML cases developing in CLL [Robertson et al. 1994; Mateu et al. 1997; Astrow, 2003; Park et al. 2009]. The present patient did not have any high-risk genetic mutations, however, overt DIC may reflect the aggressive disease manifestation. A few cases with normal karyotype or good-risk cytogenetics such as t(15;17) or inv(16) have also been reported [Molero et al. 2001; Lu et al. 2006; Hatoum et al. 2007]. Unlike the majority of patients, who have poor outcomes [Bracey et al. 1989; Robertson et al. 1994; Mateu et al. 1997], patients with good-risk cytogenetics may have good outcomes [Molero et al. 2001; Lu et al. 2006; Hatoum et al. 2007; Park et al. 2009]. However, long-term outcomes are not reported to confirm this presumption. The optimal therapy is unknown; however, given the poor overall outcome, consideration should be given to curative-intent chemotherapy followed by allogeneic stem-cell transplantation in eligible patients. National Comprehensive Cancer Network (NCCN) AML guideline 2014 recommends enrollment in a clinical trial or allogeneic stem-cell transplantation for high-risk AML including therapy-related AML (NCCN.org) [O’Donnell et al. 2014].

In conclusion, the present case highlights the rare possibility of the development of a myeloid malignancy in a patient with lymphoid malignancy. It is important to realize that fludarabine [Tam et al. 2006; Waterman et al. 2012] may uncommonly predispose to treatment-related AML. Knowledge of this rare association is the key to timely and accurate diagnosis, particularly in patients with atypical presentation. Existing literature demonstrates that AML may also develop concurrently or after the diagnosis of treatment-naïve CLL patients. Further studies of such patients have potential to provide insight into the pathogenesis of myeloid as well as lymphoid malignancies.