Dasatinib-associated follicular lymphoma in a patient with B-cell acute lymphoblastic leukaemia

Abstract

The tyrosine kinase inhibitor dasatinib is approved for the treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL). Patients on dasatinib can rarely develop a form of benign reversible reactive lymphadenopathy termed follicular lymphoid hyperplasia (FLH). Here, we describe a patient with Ph+ ALL who developed follicular lymphoma (FL) after prolonged treatment with dasatinib and who had complete remission of FL after discontinuation of dasatinib. This case suggests that dasatinib-associated FLH could be a premalignant condition that can transform into FL. Moreover, withdrawal of dasatinib may be sufficient for remission of dasatinib-associated FL.

Background

The 9;22 translocation (Philadelphia chromosome), a hallmark of chronic myeloid leukaemia (CML), is present in 15%–50% of adult acute lymphoblastic leukaemia (ALL).¹ The second-generation Abl tyrosine kinase inhibitor (TKI) dasatinib is approved for the treatment of CML and Philadelphia chromosome-positive ALL. Follicular lymphoid hyperplasia (FLH) is a rare but reversible adverse effect of long-term treatment with dasatinib (table 1).^2–9 In a case series of nine patients with chronic-phase CML who developed dasatinib-induced FLH, the median time to presentation with lymph node enlargement was 20 months after initiation of dasatinib treatment, and the median time to complete resolution of node enlargement was 1 month after discontinuation of dasatinib.² Both the mechanisms behind the development of dasatinib-associated FLH and the potential for malignant transformation of FLH remain unclear. One case of dasatinib-associated FLH was associated with clonal cytogenetic abnormalities, raising concern for a premalignant condition.² Studies examining whether patients with CML on TKI therapy have an increased risk of secondary malignancies, including lymphomas, have yielded conflicting results.^{10 11} We report a case of new follicular lymphoma (FL) in a patient with B-cell acute lymphoblastic leukaemia (B-ALL) treated with dasatinib, with complete remission after discontinuation of dasatinib therapy.

Table 1.

Summary of case reports of dasatinib-associated FLH

n	Age (years) (median)	Dasatinib dose, mg/day (n)	Location of LAD (n)	Biopsy findings	Time in months (median)			Subsequent therapy (n)
					Starting dasatinib to onset of LAD	Onset of LAD to stopping dasatinib	Stopping dasatinib to resolution of LAD
9	24–69 (52)	100 (7), 80 (1), 50 (1)	Cervical (9), inguinal (1)	FLH, one patient with clonal cytogenetic abnormality	9–35 (20)	Unknown	0.5–2.0 (1)	Nilotinib (6), none (2), ASCT (1)
1	37	100	Parotid, cervical	Follicular and interfollicular hyperplasia	8	Unknown	1	Bosutinib
3	46–62 (54)	Unknown	Cervical (3), axillary (1)	Follicular hyperplasia with vascular and mantle zone intrusion into GCs	15–24 (19)	Unknown, NA	1.5, NA, unknown	Nilotinib (1), dasatinib (1), unknown (1)
1	67	100	Cervical	Mixed paracortical and reactive follicular hyperplasia	12	‘A few months’	‘Promptly’	None
1	14	100	Parotid, cervical	Follicular and interfollicular hyperplasia	5	6	3.5	Nilotinib
2	30–49 (40)	100 (2)	Cervical	Follicular hyperplasia, reactive GCs, moderate expansion of paracortical T-zone	12–48 (30)	Unknown	Unknown	Ponatinib
1	40	Unknown	Axillary	Follicular hyperplasia, PTGC, paracortical expansion with polymorphous infiltrates, activated lymphoid cells with multilobular nuclei	5	Unknown	1	Nilotinib

All patients had a diagnosis of CML. Age is at time of diagnosis of CML.^2–8

ASCT, allogeneic stem cell transplant; CML, chronic myeloid leukaemia; FLH, follicular lymphoid hyperplasia; GC, germinal centre; LAD, lymphadenopathy; n, number of patients; NA, not applicable; PTGC, progressive transformation of germinal centres.

Case presentation

A man in his early 40s presented with fatigue, night sweats and weight loss. A submental excisional lymph node biopsy and bone marrow biopsy revealed B-ALL with 95% involvement of a 95% hypercellular marrow. He was initially started on induction therapy under the CALGB 10403 protocol with intrathecal methotrexate.¹² However, interphase fluorescence in situ hybridisation of the bone marrow sample subsequently revealed BCR–ABL1 fusion in 94.5% of nuclei, with concurrent chromosome analysis demonstrating a 9;22 translocation. These findings prompted a switch in therapy to rituximab–hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) with dasatinib 100 mg/day 1 month later. He achieved a complete molecular remission, and after four cycles of rituximab–hyper-CVAD, he was transitioned to POMP (mercaptopurine, vincristine, methotrexate and prednisone) maintenance. Four months later, POMP was held due to intolerance, but dasatinib was continued.

Twenty-seven months after initiating dasatinib, the patient developed enlarged left upper mandibular region lymph nodes, up to 2.2 cm in size by ultrasound, with no features specifically concerning for malignancy. His B-ALL remained in major molecular remission with undetectable BCR–ABL1 transcripts. In the following 6 months, he noticed additional lymphadenopathy in the left cervical and supraclavicular regions. Fine-needle aspiration (FNA) of a supraclavicular lymph node revealed findings consistent with a benign reactive process. Because he was tolerating dasatinib well and remained in complete molecular remission with consistently negative peripheral blood BCR–ABL1 PCR, the decision was made to continue dasatinib therapy rather than switching to an alternative TKI. His cervical lymphadenopathy continued to progress over the following months, accompanied by the appearance of new inguinal lymphadenopathy and constitutional symptoms.

Approximately 16 months after the initial appearance of lymphadenopathy, ¹⁸F-fluoro-deoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/CT showed widespread hypermetabolic cervical, axillary, mediastinal and inguinal lymphadenopathy (figure 1A, left). He underwent an excisional biopsy of a left neck lymph node with pathology revealing FL.

Figure 1.

Imaging and pathology of dasatinib-associated follicular lymphoma. (A) ¹⁸F-FDG PET/CT coronal sections demonstrating hypermetabolic cervical and axillary lymphadenopathy before (left) and 9 months after (right) discontinuation of dasatinib. Arrows indicate areas of hypermetabolic lymphadenopathy. (B) Morphology and immunohistochemistry of excisional lymph node biopsy, shown at ×100 original magnification (smaller images) and ×400 original magnification (insets). (C) Flow cytometry of excisional lymph node biopsy, highlighting monotypic B cells (dark green), polytypic B cells (olive green) and T cells (orange). ¹⁸F-FDG, ¹⁸F-fluoro-deoxyglucose; PET, positron emission tomography.

Investigations

In the excisional biopsy of his left neck lymph node, the lymph node architecture was effaced by a vaguely nodular infiltrate (figure 1B, left) that was composed of a mixture of centrocytes and centroblasts, with >15 centroblasts per high-power field (figure 1B, left inset). The atypical cells were associated with abundant CD21-positive follicular dendritic cell meshworks and coexpressed CD20, CD10, BCL6 and BCL2 with increased Ki-67 proliferation index (figure 1B, middle and right insets). Flow cytometry demonstrated a lambda-restricted CD10-positive B-cell population in a background of polytypic B cells (figure 1C). Molecular studies demonstrated clonal immunoglobulin gene rearrangement. Taken together, these findings were diagnostic of FL, WHO grade 3a. Recurrence of B-ALL was excluded by the mature cytomorphology and phenotype of the FL cells as well as the absence of terminal deoxynucleotidyl transferase (TdT) staining by immunohistochemistry (not shown). Bone marrow biopsy showed no involvement of B-ALL or B-cell lymphoma, and qPCR was negative for BCR–ABL1 fusion transcripts (limit of detection 0.0025%).

Given the patient’s history of B-ALL, the clonal relationship of the two neoplasms was evaluated. Immunoglobulin gene rearrangements were assessed by next-generation sequencing, and sequences of the clonally rearranged IGH and IGK genes were compared. The B-ALL demonstrated clonal rearrangement of both IGH alleles and a single IGK allele. In contrast, the FL demonstrated clonal rearrangement of a single IGH allele and both IGK alleles. The clonal sequences identified in the FL and B-ALL were distinct, and neither clone was present in the other sample at a detectable level (limit of detection 0.02%). Furthermore, based on the IGHV, IGHJ, IGKV and IGKJ gene usage, the FL clone could not have evolved from the B-ALL clone or vice versa. Thus, the two neoplasms were entirely distinct.

Differential diagnosis

Although the differential for lymphadenopathy includes infectious and autoimmune aetiologies, the excisional biopsy of the patient’s left neck lymph node confirmed a diagnosis of FL.

Treatment

Dasatinib was discontinued 1 month after the PET/CT. His lymphadenopathy markedly improved within a few weeks and completely resolved 2 months after discontinuation. He was switched to ponatinib 30 mg/day.

Outcome and follow-up

Since starting ponatinib, he has not had any recurrence of palpable lymphadenopathy. A repeat ¹⁸F-FDG PET/CT 9 months after discontinuation of dasatinib showed no FDG-avid disease (figure 1A, right). His peripheral blood BCR–ABL1 PCR has remained negative 16 months after starting ponatinib.

Discussion

This case raises the possibility that dasatinib-associated FLH can undergo malignant transformation to FL. Our patient had been treated with dasatinib for a relatively long period of time (43 months) prior to diagnosis of FL. He presented with lymphadenopathy after 27 months of dasatinib therapy, consistent with prior reported cases of dasatinib-associated FLH, which occurred 5–48 months after initiation of dasatinib (table 1). However, in most reported cases, dasatinib was discontinued soon after onset of lymphadenopathy, whereas our patient continued dasatinib for another 16 months before he was diagnosed with FL. Given that his FNA biopsy during that time period demonstrated only benign reactive changes, it is possible that he initially had dasatinib-associated FLH and that continued exposure to dasatinib provided the necessary conditions for FLH to transform into the FL seen on his excisional biopsy. While infections and autoimmune conditions can cause benign reactive lymphadenopathy, the lack of other signs or symptoms consistent with these conditions, the evolution to FL and the resolution of his lymphadenopathy on discontinuation of dasatinib strongly argue against these alternative aetiologies. Prolonged exposure to dasatinib is not sufficient for transformation to FL, as another case report described a patient who continued dasatinib for 18 months after onset of lymphadenopathy, with excisional biopsy at that time still showing FLH.⁴ Nonetheless, our patient’s course raises the possibility that prolonged exposure to dasatinib increases the risk of transformation to FL. While there are reports of resolution of lymphadenopathy despite continuation of dasatinib therapy,⁹ this case highlights the importance of discontinuing dasatinib or at least closely monitoring patients who develop lymphadenopathy on dasatinib, given the possibility of malignant transformation.

We suggest that the development of FL in our patient was related to dasatinib, given the known association of dasatinib with FLH, as well as the complete remission of his FL with discontinuation of dasatinib. Patients with concurrent FL and ALL have been rarely reported;¹³ however, sequencing of our patient’s FL and B-ALL revealed two separate clones that could not have evolved from one another, demonstrating that the two neoplasms are entirely distinct. Moreover, FL was not noted in our patient’s excisional lymph node biopsy on initial diagnosis of B-ALL, making it less likely that he had undiagnosed FL at that time. Another possibility is that he developed FL after his diagnosis of B-ALL but independently of dasatinib. Adults with ALL have increased risk of second malignancies including non-Hodgkin’s lymphoma, likely due to a combination of genetic and environmental factors including chemotherapy.¹⁴ We cannot exclude the possibility that his FL and ALL have a common stem cell origin or developed independently as a result of predisposing genetic and environmental factors, although the timing of onset and resolution of his lymphadenopathy are consistent with an association with dasatinib.

Importantly, discontinuation of dasatinib led to a complete remission of the FL in our patient. While spontaneous regression of FL can occur,¹⁵ the timing in this case strongly suggests that his FL was dependent on continued exposure to dasatinib. Moreover, switching to ponatinib did not result in recurrence of lymphadenopathy, suggesting that dasatinib promotes FL via a mechanism that is not shared by ponatinib. Similarly, in reported cases of dasatinib-associated FLH, switching to nilotinib, bosutinib or ponatinib did not result in recurrence of lymphadenopathy (table 1). While the mechanisms behind the pathogenesis of dasatinib-associated FLH and FL remain unclear, discontinuation of dasatinib has led to resolution of lymphadenopathy in dasatinib-associated FLH as well as FL. Thus, biopsy findings consistent with FL in a patient on dasatinib should prompt consideration of dasatinib-associated FL, and discontinuation of dasatinib should be attempted. As demonstrated in this case, discontinuation of dasatinib may lead to rapid resolution of lymphadenopathy, and the patient may be spared from chemoimmunotherapy or other conventional treatments for FL.

In summary, dasatinib-associated FLH occurs through mechanisms that are not completely understood. We report a case in which a patient with B-ALL on dasatinib developed FL that regressed after discontinuation of dasatinib, suggesting that dasatinib can be associated with the development of FL, and that dasatinib-associated FLH might be a premalignant condition. This case report expands the differential that needs to be considered in patients who develop lymphadenopathy on dasatinib. Moreover, this case further demonstrates the importance of discontinuing dasatinib in patients with dasatinib-associated FLH and additionally reveals that discontinuation of dasatinib may be sufficient to induce regression of dasatinib-associated FL.

Learning points.

• A patient with B-cell acute lymphoblastic leukaemia (B-ALL) developed follicular lymphoma (FL) while on dasatinib therapy.

• The FL was clonally distinct from the patient’s B-ALL.

• The FL regressed on discontinuation of dasatinib.

• Dasatinib may be associated with the development of FL.

• Discontinuing dasatinib may induce regression of dasatinib-associated FL.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).