Summary letter for adverse event report. Male aged 44 yrs

Initial Presentation:
20 July 2001: blood test performed for assessment of testicular swelling (ultrasound showed varicocele and epididymal Cyst). White cell count 176 x 10e9/L, platelets 247, Hb 110 g/L, peripheral blood count 1%. Bone marrow consistent with chronic phase of CML, blast count 3%. Cytogenetics Philadelphia chromosome in 100% and second abnormality t(17:22) in all cells (? clonal evolution). Spleen 12 cm. No significant past history of medical or surgical illnesses. Autologous peripheral blood stem cells collected and stored. Treated with hydroxyurea and imatinib 600 mg daily from August 2001.

January 2002: complete cytogenetic remission.

July 2004: first quantitative Q-PCR (Adelaide) 0.03%
Oct 2004 - Jan 2005: rising PCR 0.1% then 0.29% so imatinib increased to 800 mg/d.
Oct 2005: Started Pegylated interferon on CML5 trial.
Oct 2006: Continues on PegIFN trial, Q-PCR down to 0.05%
2007: Continues PegIFN + Imatinib 800 mg/d
May 2008: Elected to cease PegIFN after 2 1/2 yrs on treatment. Q-PCR 0.03%. Continues imatinib
2008-2012 - Well, continues imatinib but troubled by muscle cramps.
April 2012 - Elected to change from imatinib to dasatinib because of muscle cramps. Q-PCR 0.01%

History of dasatinib useage:
2/5/2012 : started dasatinib 100 mg daily
19/5/2012: admitted to hospital with one week history of breathlessness, i.e. after 10 days of dasatinib developed symptoms. Chest x-ray showed marked increase in interstitial markings and patchy airspace changes in the right lower lobe and left mid-zone suggestive of interstitial oedema or atypical infection. Markedly elevated BNP (brain natriuretic peptide) 1277 (Normal < 125). Treated with diuretics (Frusimide), prednisolone 25 mg daily and temporary cessation of dasatinib. Restarted dasatinib on 30/5/2012 at 50 mg daily, with no recurrence of symptoms or signs and increased to 100 mg daily on 17/7/2012.

July 2012-March 2013: generally well and continued on dasatinib 100 mg daily. Q-PCR remains low at 0.01%
March 2013 : presents with three month history of lymph node swelling in the left upper cervical region of the neck. Otherwise well with no symptoms and no throat infection. 2 adjacent nodes approximately 2 cm identified on palpation but no lymphadenopathy elsewhere. Blood count normal. Excision biopsy of one node shows florid reactive changes, report shows:

MICROSCOPIC:
The lymph node has scattered large reactive lymphoid follicles with large
irregularly-shaped germinal centres and well-defined surrounding mantle zones.
The remaining interfollicular/paracortical zones contain large numbers of
immunoblasts with single to multiple amphophilic nucleoli. No obvious Hodgkin
Reed-Sternberg (HRS) cells are seen. No viral inclusions or multinucleated
giant cells are seen.

Immunohistochemistry:
CD3: highlights small T-cells, predominantly in
interfollicular/paracortical zones.
CD20: highlights B-cell follicles as well as interfollicular/paracortical
immunoblasts. BCL2: negative in reactive germinal centres; weakly positive in
immunoblasts. CD30: highlights occasional scattered immunoblasts. CD15:
highlights occasional scattered cells, generally small to intermediate in
size, as well as some larger cells likely histiocytes. No convincing staining
of immunoblasts. CD10: highlights germinal centres.
Cyclin D1: negative.
MPO: negative.
Ki67 index: high in germinal centres, low in mantle zones, and moderate in
interfollicular/paracortical zones.

COMMENT/SUMMARY:
The lymph node has non-specific florid follicular and paracortical reactive
changes. The cause for the reactive changes is not evident; clinical
correlation is required. Viral stains to follow. Please also correlate with
microbiology, flow cytometry and cytogenetics results.

Flow cytometry: The tissue was lymphoid gated. Lymphocytes show a mixture of T and B cells. T-cells show a normal CD4:8 ratio. B cells are polyclonal. No diagnostic features.

Following the biopsy the adjacent lymph node spontaneously resolved.

March 2014: clinically well but reports enlarged lymph nodes in the right upper cervical region present approximately 6 months, relatively stable in size. No other abnormal physical findings.

Blood test results from 24/3/2014

Hb 141 g/L, WCC 5.2 x109/L, platelets 179 x 109/L, neut 2.8, lymph 1.6, mono 0.6, eos 0.2,
sodium 138 mmol/L, potassium 5.0 mmol/L, bicarbonate 26 mmol/L, urea 6.8 mmol/L, creatinine 108 umol/L, eGFR 67 ml/min
bilirubin 6 umol/L (3 - 20), AST 34 U/L (12 - 36), ALT 25 U/L (< 55), GGT 36 U/L (12 - 64), ALP 81 U/L (41 - 119), albumin 44 g/L (35 - 52)
BCR-ABL 0.01% (19/12/13).

Current Plan: Watch and wait, possibly consider core biopsy of nodes.

I did a quick literature search and to my surprise found a publication from Roux et al (Reversible lymph node follicular hyperplasia associated with dasatinib treatment of chronic myeloid leukemia in chronic phase) which sounds very similar to my patient. The authors recommend ceasing dasatinib but without good evidence that its necessary and so I have continued my patient on dasatinib pending further information/advice.

We have indeed document different cases in France with a similar history.

This is likely to be induecd by Dasatinib treatment and requires its definitive cessation.

In the index case I had in my center (histopathology, cytogenetics and molecular findings are shown in our Blood brief report), we were quite nervous to find some choromosomal abnormalities in the lymph node biopsy (3 metaphases) and B-Cell clonal analysis was positive. All metaphases were Philadelphia negative. Dasatinib was immediately withdrawn. This patient is now on Nilotinib 2 years fater , is in MR4 and no reccurence of any lympho node.

I would absolutely go for a lymph node biopsy to ensure that this is not a local blast crisis, and if not withdraw Dasatinib and switch to another TKI.

Best Regards,

Franck Nicolini
Lyon,
France

I have 3 similar presenting patients. One with exactly the same findings whose lymph nodes come and go and have been biopsied on several occasions. She had a 0.0032% or better response to dasatinib for several years and elected to come off therapy. Nodes are gone and she continues about a year out with her CML response on monitoring.
The second one is a male who was on nilotinib who developed a similar picture. Initial LN biopsies suggested reactive, but eventually a diagnosis of angioimmunoblastic T-cell NHL was made. He was treated with chemo and responded well and has been off nilotinib now for about 17 months sustaining MMR.
The third is a male with about a 20 year history of CML, failed IFN, then HHT and accelerated on imatinib. Went on the START A study and remains with CMR after a decade. Nodes in neck about 6 years ago, initially felt to be reactive but eventually turned out to have a high grade follicular NHL treated successfully with CHOP-R and involved field XRT. Dasatinib was never stopped.
I think my message is that you can continue dasatinib as there is no cause and effect proven, but the vigilence with perhaps repeat biopsies is necessary as things change or biopsies may not get to the heart of things.