Accepted Manuscript Palbociclib-induced thrombotic microangiopathy in metastatic breast cancer surviving for 18 years: A case Report and Review of the literature. Hanan Raiss, Julien Peron, Sophie Tartas, Veronique Trillet-Lenoir, Gilles Freyer, Hassan Errihani PII: S1526-8209(17)30072-1 DOI: 10.1016/j.clbc.2017.10.001 Reference: CLBC 689 To appear in: Clinical Breast Cancer Received Date: 5 February 2017 Revised Date: 13 July 2017 Accepted Date: 1 October 2017 Please cite this article as: Raiss H, Peron J, Tartas S, Trillet-Lenoir V, Freyer G, Errihani H, Palbociclibinduced thrombotic microangiopathy in metastatic breast cancer surviving for 18 years: A case Report and Review of the literature., Clinical Breast Cancer (2017), doi: 10.1016/j.clbc.2017.10.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 ACCEPTED MANUSCRIPT Palbociclib-induced thrombotic microangiopathy in metastatic breast cancer surviving for 18 years: A case Report and Review of the literature. Hanan Raiss1, Julien Peron2, Sophie Tartas2, Veronique Trillet-Lenoir2, Gilles Freyer2, Hassan Errihani1 1 RI PT Department of Medical Oncology, National Institute of Oncology, CHU Rabat, Mohamed V University, Avenue Allal Al Fassi, Madinat Al Irfane, 10000 Rabat, Morocco. 2 Department of Medical Oncology, Lyon University Hospital, 165, Chemin du Grand Revoyet, 69495 Pierre-Bénite cedex, France. Hanan Raiss1, E-mail: raiss.hanan@gmail.com, Tel.: +212 6 66 16 51 33, Corresponding author Sophie Tartas2, E-mail: sophie.tartas@chu-lyon.fr SC Julien Peron2, E-mail: julien.peron@chu-lyon.fr Véronique Trillet-Lenoir2, E-mail: veronique.trillet-lenoir@chu-lyon.fr M AN U Gilles Freyer2, E-mail: gilles.freyer@chu-lyon.fr Hassan Errihani1, E-mail: errihani5@gmail.com CLINICAL PRACTICE POINTS: TE D • Thrombotic microangiopathy (TMA) is a group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury due to thrombi in the microcirculation. • An extensive variety of drugs, including certain antitumor agents, have been associated with TMA. • We report a case of palbociclib-induced TMA in a 65-years-woman followed for metastatic breast cancer. EP Two weeks after palbociclib initiation, the patient was admitted to the hospital for acute neurological disorders, hemolytic anemia and thrombocytopenia. Palbociclib was immediately discontinued. Thereafter, biological abnormalities and neurological disorders gradually improved. • To the best of our knowledge, this is the first case of palbociclib-induced TMA. AC C Keywords : Thrombotic microangiopathy (TMA); Palbociclib; Drug-induced TMA ; Metastatic breast cancer. Introduction: Thrombotic microangiopathy (TMA) was first described in 1924 by Moschcowitz [1], it is a group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and variable end-organ damage due to thrombi in the microcirculation [2]. TMA includes thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndromes (HUS) [3]. Etiologies are multiples. Drug-induced TMA (DITMA) is rare, but it causes significant morbidity and mortality [4]. Many different drugs have been reported to cause TMA, including cytotoxic chemotherapy and targeted agents [5]. Palbociclib is an oral inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 which play a crucial role in cell cycle regulation [6, 7]. It was recently approved by U.S.Food and Drug Administration in combination with 2 ACCEPTED MANUSCRIPT fulvestrant for the treatment of estrogen receptor (ER) positive, human epidermal growth factor receptor (HER2) negative advanced or metastatic breast cancer progressing after prior endocrine therapy [8], and in the combination with letrozole as first line treatment in post-menopausal women with ER-positive, HER2negative advanced breast cancer [9]. RI PT Here we report a case of palbociclib-induced TMA in a 65-years-woman followed for metastatic breast cancer at age of 47 years. To our knowledge, this is the first case to describe the association of TMA with palbociclib since palbociclib was approved by the US Food and Drug Administration. Case study: SC This case report concerns a patient who was diagnosed in 1998 at the age of 47years, with a bilateral invasive lobular carcinoma of the breast. ER and progesteron receptors were strongly expressed in the tumor biopsy, and HER2 status was negative. M AN U Bone scan showed an increased uptake of the isotope in the right iliac bone. Bone biopsy was consistent with metastasis from breast cancer. Radical mastectomy was performed on the left breast, and lumpectomy was performed on the right breast combined with lymph node dissection in both sides. Then she received post lumpectomy radiotherapy with regional nodal irradiation, radiotherapy to the left chest wall and to the pelvis. Tamoxifen was started in 08/1998. Eight months after the start of tamoxifen, bone scan revealed new and progressive bone metastases. The patient received multiple treatment lines (table 1). The last one was oral metronomic cyclophosphamide in combination with methotrexate given from 11/15 to 02/16. From February 2016, the patient received palbociclib in combination with fulvestrant. AC C EP TE D Two weeks after palbociclib initiation, the patient was admitted to the hospital for acute neurological disorders. Physical examination revealed a grade 4 hypertension, fluctuating aphasia, and a right ataxic hemiparesis. The cerebral CT-scan was normal. Laboratory tests (Table 2) showed grade 2 anemia (hemoglobin: 8.3g/dl), grade 3 thrombocytopenia (platelet count: 41 G/l), elevated serum creatinine (106 µmol/l, while the Baseline was 79 µmol/l), elevated lactate dehydrogenase (500U/l), and decreased haptoglobin. The peripheral blood smear showed 1% schistocytes. Fluctuating neurological disorders, blood pressure decompensation and biological findings during the treatment with palbociclib led to the suspicion of DITMA. Palbociclib was immediately discontinued. Antigenic dosage in serum of factor H and B was increased, while C3, C4 and CH50 levels were normal. The Anti-neutrophil cytoplasmic antibodies ANCA and ADAMTS13 were not elevated. A cerebral magnetic resonance imaging showed multiple small supra and infratentorial ischemic lesions, which were not systematized to an arterial territory. These lesions are localized in the both cerebral hemispheres, predominantly in the left one (Figure 1). Transthoracique cardiac ultrasonography and supra-aortic arteries ultrasonography were normal. After the cessation of palbociclib, biological abnormalities gradually improved. Aphasia and right hemiparesis also slightly improved. Hypertension remained uncontrolled (systolic pressure over 200mmgh) and it was necessary to introduce an angiotensin converting enzyme inhibitor in combination with calcium antagonists. One month later, the patient was readmitted because her general condition was deteriorating. Neurological disorders were not completely resolved. The patient was not eligible for any additional antineoplastic treatment, and died one month later. Discussion: 3 ACCEPTED MANUSCRIPT Thrombotic microangiopathy (TMA) syndromes are defined clinically by microangiopathic hemolytic anemia, thrombocytopenia, organ injury and pathologically by arteriolar and capillary thrombosis [10]. RI PT HUS is described by renal failure, microangiopathic haemolytic anemia and varying degrees of thrombocytopenia. TTP is characterized by thrombocytopenia, microangiopathic haemolytic anaemia, neurologic deficits, renal failure, and fever. Neurologic abnormalities are more predominant with TTP, while renal insufficiency is the most prominent sign in HUS [11, 5]. TMA can be idiopathic or secondary to infections, bone marrow transplantation, certain autoimmune conditions, malignant diseases,, and various drugs [12]. Many different drugs have been reported to cause TMA, including immunosuppressants, anti-aggregating agents, and cytotoxic chemotherapies [5]. M AN U SC In contrast to primary TTP, in which a severe deficiency of von Willebrand factor-cleaving protease (VWFcp), ADAMTS13, is presumed to be the main pathophysiological mechanism [13], the mechanism of DITMA is unknown, for nearly all drugs [3]. Two Mechanisms of adverse drug reactions have been suggested: immunologic reactions and dose-or duration-related toxic reaction [10]. The association between TMA and several chemotherapy drugs has been described, including mitomycine C and gemcitabine [5]. The incidence of mitomycine C-induced TMA varies between 0.015 and 0.31%. The prognosis of mitomycine C induced TMA is poor, with 75% mortality mostly related to renal failures [11, 5]. The incidence of gemcitabine-induces TMA ranges between 0.25 and 0.4%, with a mortality as high as 60% [5]. Other chemotherapy drugs can cause TMA, including bleomycin, cisplatin, 5-fluorouracil [14], and oxaliplatin [15]. TE D Among anteneoplastic targeted molecular therapies, drugs targeting the VEGF pathway are the best known to induce TMA [5]. TMA has also been described with other antineoplastic agents including: immune therapies and imatinib [5]. EP To our knowledge, this is the first report of a palbociclib induced TMA. AC C Palbociclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). CDK4/6 and cyclin D play a crucial role in cell cycle regulation by phosphorylation of the retinoblastoma protein (Rb), which inactivates Rb function as a tumor suppressor [6, 7, 16]. The safety and efficacy of palbociclib in combination with fulvestrant was established in the PALOMA-3 trial. The results of that trial showed that the combination of palbociclib plus fulvestrant was associated with significant improvements in progression-free survival for patients with ER-positive, Her2 negative metastatic breast cancer progressing after prior endocrine therapy compared with fulvestrant plus placebo. In this trial, neutropenia, anemia and thrombocytopenia were more frequent in the palbociclib group than in the control group [17]. In the palbociclib plus fulvestrant group, 25% of patients had grade 1-2 anemia, and 3% had grade 3 anemia. In contrast, 9% of patients treated with fulvestrant plus placebo had grade 1-2 anemia, and 2% had grade 3 anemia. Grade 3-4 thrombocytopenia was reported in among 3% of patient receiving palbociclib versus no case in the placebo group. Grade 3 hypertension was found in 2% of patient treated with the combination palbociclib plus fulvestrant [17]. 4 ACCEPTED MANUSCRIPT PALOMA 1 and 2, are respectively a phase 2 and a phase 3 trial comparing palbociclib plus letrozole versus placebo plus letrozole as first line treatment for post-menopausal women with ER+/HER2- advanced breast cancer. Both trials reached their primary endpoint by demonstrating an improvement in progression-free survival. The most frequent adverse event was neutropenia. As in the PALOMA-3 trial, anemia and thrombocytopenia were more frequent in the palbociclib group. No case of MAT was reported in the three trials [7, 6, 18]. RI PT Our patient had already been treated with fulvestrant for three years with good tolerance and has never presented a TMA. However she received multiple treatment lines between march 2014 and the onset of the palbociclib plus fulvestrant combination, which may have promoted the occurrence of TMA. SC Optimal treatment for DITMA is unclear. Drugs suspected to have induced TMA must be discontinued immediately, and blood pressure should be controlled. Treatment modalities used in other forms of TMA have been used empirically in DITMA such as Plasmapheresis, immunoadsorption, immunomodulatory therapies, or plasma exchange therapy with unclear efficacy [4, 2, 11]. M AN U Conclusion Despite that anemia and thrombocytopenia are known side effects of palbociclib, it’s important for clinicians to be aware that MAT may occur in patients who are treated by palbociclib, because an early diagnosis may be vital. Consent Competing interest TE D Obtained. The authors declare that they have no competing interests. Funding Abbreviations EP The authors declare that they didn’t receive any funding. AC C TMA: thrombotic microangiopathy; TTP: thrombotic thrombocytopenic purpura; HUS: hemolytic-uremic syndromes; DITMA : Drug-induced TMA; ER: estrogen receptor, HER2: humman epidermal growth factor receptor; CD4/6: cyclin-dependent kinases 4 and 6; RB: retinoblastoma protein; CT-scan: computed tomography scan. ADAMTS13: a disintegrin and metalloprotease with thrombospondin type I repeats-13. References: 1. Tada K, Ito K, Hamauchi A, Takahashi K, Watanabe R, Uchida A, Abe Y, Yasuno T, Miyake K, Sasatomi Y, Nakashima H. Clopidogrel-induced Thrombotic Microangiopathy in a Patient with Hypocomplementemia. Intern Med. 2016;55(8):969-973. 2. Iams W, Beckermann KE, Neff AT, Mayer IA, Abramson VG. Thrombotic microangiopathy during docetaxel, trastuzumab, and carboplatin chemotherapy for earlystage HER2+ breast cancer: a case report. Med Oncol. 2013;30(2):568. 5 ACCEPTED MANUSCRIPT 3. Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood. 2015 Jan 22;125(4):616618. 4. Pisoni R, Ruggenenti P, Remuzzi G. Drug-induced thrombotic microangiopathy:incidence, prevention and management. Drug Saf. 2001;24(7):491-501. RI PT 5. Blake-Haskins JA, Lechleider RJ, Kreitman RJ. Thrombotic microangiopathy with targeted cancer agents. Clin Cancer Res. 2011 Sep 15;17(18):5858-5866. SC 6. 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Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of 6 ACCEPTED MANUSCRIPT hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.Lancet Oncol. 2016 Apr;17(4):425-439. AC C EP TE D M AN U SC RI PT 18. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON,Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Diéras V, Slamon DJ. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. 7 ACCEPTED MANUSCRIPT Table 1: Treatment regimens Oct2015-Nov2015 Dec2016-Feb2016 RI PT Apr2014-Sep2015 Treatment regimens Tamoxifen Anastrozole Letrozole Megestrol acetate Doxorubicin-Paclitaxel combination No treatment Capecitabine Fulvestrant Exemestane and everolimus combination Eribuline Metronomic oral methotrexate and cyclophosphamide combination SC Time Aug1998-Mar1999 Apr1999-May1999 Jun1999-Sep2000 Oct2000-Dec2000 Jan2001-Apr2001 May2001-Oct2005 Nov2005-Jan2011 Feb2011-Mar2014 12.4 10.5 8.3 7.5 6.8 11.7 10.5 11.6 9.4 10.2 10 Platelet count (G/L) 128 PNN (G/L) Creatinine (umol /L) 3.19 81 Creatinine Clearance (ml/min) 61 103 3.25 79 63 41 37 37 32 36 49 70 105 142 1 1.01 1 1.13 0.99 1.19 1.12 1.30 1.85 105 105 93 103 93 90 82 91 97 44 45 52 46 52 54 60 53 49 AC C EP Day pre-Palbo Day of administration Day 15 Day 17 Day 18 Day 20 Day 21 Day 22 Day 25 Day 27 Day 32 Hemoglobin (g/dl) TE D Time M AN U Table 2 : Laboratory data Figure 1: Magnetic Resonance image reveals multifocal cortical and subcortical hyperintensities