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Toxicities in B-Cell Non-Hodgkin Lymphoma—New Agents, New Pitfalls

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Toxicities in B-Cell Non-Hodgkin Lymphoma—New Agents, New Pitfalls review memo (2019) 12:12–16 https://doi.org/10.1007/s12254-018-0466-1 Toxicities in B-cell non-Hodgkin lymphoma—new agents, new pitfalls Thomas Spanberger Received: 7 July 2018 / Accepted: 30 November 2018 / Published online: 21 December 2018 © Springer-Verlag GmbH Austria, part of Springer Nature 2018 Summary Immunochemotherapy has long been the lysis syndrome. The drug also causes high rates of backbone of all treatment for B-cell non-Hodgkin hematological toxicities, especially neutropenia. lymphoma. These therapies led to long-term dis- ease control or even cure for some patients. How- Keywords Ibrutinib · Idelalisib · Venetoclax · Tumor ever, these treatments also caused—sometimes se- lysis syndrome · BTK inhibitor vere—toxicities and deterioration of the quality of life. Novel agents targeting the B-cell-receptor pathway Introduction and bcl2 have made great inroads in the treatment of mature lymphoid neoplasms. These new agents Non-Hodgkin lymphoma comprise a variety of malig- present themselves with a wide variety of new tox- nant neoplasms derived from B-cells, T-cells, or NK- icities, which have to be taken into account when cells. They comprise 4.3% of all new cancer diagnoses being administered to our patients. Hematological and are the cause of 3.3% of all cancer deaths [1]. toxicities are very common. All new agents lead to Immunochemotherapy has been the backbone of various levels of immune suppression or immune treatment of non-Hodgkin lymphoma for 20 years, modulation, which is often not easily quantifiable. leading to long-term disease control or even cure for Opportunistic infections such as progressive multifo- some patients [2, 3]. However, this efficacy came at cal leukoencephalopathy, pneumocystis pneumonia, the price of sometimes severe toxicities. other mycotic infections, cytomegalovirus infections In recent years, new targeted agents have increased and pneumocystis pneumonia have been described, their role in the treatment of non-Hodgkin lymphoma. sometimes with fatal outcome. Ibrutinib shows in- This review will focus on non-chemotherapeutic creased risk of atrial fibrillation. It also increases the agents used in the treatment of non-Hodgkin lym- risk of bleeding, making theproperanticoagulatory phoma, including the Bruton’s tyrosine kinase(BTK)- management of patients developing atrial fibrilla- inhibitor ibrutinib, the phosphatidylinositol 3-kinase tion under treatment a challenge. Idelalisib causes inhibitors idelalisib and copanlisib, and the BCL2-in- severe, sometimes fatal immune-mediated end-or- hibitor venetoclax. gan toxicities, especially colitis, pneumonitis, and transaminitis. Copanlisib leads to metabolic changes, Ibrutinib namely episodes of hyperglycemia and arterial hyper- tension. Venetoclax has caused clinically significant Ibrutinib is a Bruton tyrosine kinase inhibitor. It is tumor lysis syndrome. The introduction of a pro- indicated for the treatment of CLL in the first line in longed ramp-up phase of step wise dose escalation cases with a del17p or tP53 mutation. In all other has decreased the rate of clinically significant tumor CLL patients it is indicated when the patient has failed, or is deemed an unsuitable candidate for im- munochemotherapy. It is also used in recurrent or refractory mantle cell lymphoma and Waldenstrom T. Spanberger, MD () 1. Med. Abteilung, Wilhelminenspital, macroglobulinemia. Montleartstraße 37, 1060 Vienna, Austria In single-agent ibrutinib therapies, grade 3–4 neu- [email protected] tropenia occurred in approximately 15% of patients. 12 Toxicities in B-cell non-Hodgkin lymphoma—new agents, new pitfalls K review Grade 3–4 thrombocytopenia occurred in approxi- a well-controlled anti-coagulation therapy, treatment mately 10% of patients [4]. alternatives, e.g. rituximab/idelalisib or venetoclax In a recently published retrospective analysis of 378 should be considered. Also, in patients with a his- patients treated for various hematological disorders, tory of major bleeding due to a cause which can not serious (grade ≥3) infections occurred in 11% (43) of be adequately treated or modified, ibrutinib should patients, including a surprisingly high portion of inva- be avoided. sive fungal infections (27.2% of all serious infections) [5], among them PCP, cryptococcal infection and in- Idelalisib vasive aspergillosis. There have been case reports of PML [6]. Generally, ibrutinib moderately increases Idelalisib is a phosphatidylinositol-3-kinase inhibitor the risk of infection, and, if no other risk factors are used in the treatment of CLL and refractory follicular present, anti-infectious prophylaxis is not indicated lymphoma. [7]. It has shown strong efficacy in these indications, The most common non-hematological, non-infec- but severe toxicities have hampered its use. tion adverse events include diarrhea, atrial fibrillation, Rates of severe neutropenia in clinical trials were hypertension, and bleeding/bruising [8]. approximately 30%. However, the rates of febrile neu- Diarrhea, the most commonly observed AE, is tropenia were low (3%) [15, 16]. mostly mild, and generally self-limited without ad- In a retrospective analysis, 2.5% of patients under ditional therapy. Dose reduction or treatment dis- idelalisib treatment developed PCP [17], leading to the continuation is only needed in a small minority of recommendation of PCP prophylaxis for all patients patients [8]. from start of idelalisib therapy up to 2–6 months after The risk of atrial fibrillation increases significantly discontinuation [7] Similarly, an increased rate of CMV under treatment with ibrutinib, with incidence rates infections has been noted, and regular CMV monitor- of 5–8%. The risk to develop AF under ibrutinib treat- ing should be performed [7]. ment increases with the same risk factors as in the Immune-mediated colitis usually appears as watery general population (hypertension, structural heart diarrhea [18]. In all, 14–19% of all patients receiving disease, male sex, age) [7]. idelalisib develop grade 3–5 diarrhea [9]. Idelalisib- The management of atrial fibrillation in patients caused diarrhea can be separated into two groups: an with ibrutinib is challenging. If the severity according early (usually within the first 2 months of treatment), to CTCAE is ≥3, ibrutinib should be discontinued un- self-limiting form which responds well to anti-motility til control of AF, after which ibrutinib re-exposure is drugs, and a late, more severe form which does not feasible. Even after a second relapse, a re-challenge respond to anti-motility drugs [9]. at a lower dose can be considered [9]. Verapamil, In grade 1 and 2 diarrhea, idelalisib may be con- diltiazem and amiodarone should be avoided due to tinued, and symptomatic treatment is advised. How- drug–drug interactions with ibrutinib. The need for ever, grade 2 diarrhea occurring late or not respond- anti-coagulation due to atrial fibrillation needs to be ing to anti-motility drugs should be treated similar to balanced against the risk of bleeding, which is in- more severe forms. In patients with grade 3 or 4 di- creased by ibrutinib. The CHA2DS2-VASC-Score and arrhea, or those with grade 2 diarrhea not responding theHAS-BLEDscoremaybevaluableindetermining to treatment, idelalisib should be immediately dis- the most beneficial course of action in these patients continued, and workup to exclude infectious causes [10]. should be performed. Once infectious causes are ex- In early studies, both an increased overall bleed- cluded, treatment with topical and/or oral and/or in- ing risk and an increased risk of major bleeding was travenous steroids should be started. After diarrhea reported [11, 12].A recent meta-analysis found sig- resolves, in grade 2–3 diarrhea, idelalisib may be re- nificantly increased risk of bleeding of any severity, instated at a lower dose per clinical judgment in indi- but rates of major bleeding were not increased [13]. vidual cases. Prophylactic concomitant use of budes- While vitamin-K antagonists were allowed initially in onide may be warranted [19]. the first clinical studies, they were excluded from fur- Pneumonitis has been seen at rate of approximately ther trials after several intracerebral bleeding events 4% in patients receiving idelalisib, and several fatal [14].A portion of patients in subsequent trials used cases have been reported [9]. Therefore, extreme cau- other anticoagulants and/or anti-platelet agents, and tion has to be taken in patients under treatment re- the rate of major bleeding events in these patients porting respiratory symptoms. If a mild persistent was low. However, there is no definitive study on cough, a 5% drop in oxygen saturation, increased dys- the safety of the combination of anticoagulants and pnea under exertion, or pulmonary infiltrates in imag- ibrutinib, and the individual risk has to be taken into ing occur, idelalisib should be discontinued immedi- account before starting such a patient with ibrutinib ately, and patients should undergo a comprehensive [14]. Therefore, patients already on non-optimally ad- workup including a high-resolution chest CT. Bron- justed OAC for treatment of pre-existing AF should not choscopy and BAL needs to be evaluated individually. be treated with ibrutinib, and, even in patients with Systemic prednisolone should be started at a dose of K Toxicities in B-cell non-Hodgkin lymphoma—new agents, new pitfalls 13 review Fig. 1 Treatment algo- rithm for tumor lysis syn- drome. TLS tumor lysis syndrome, LDH lactate de- hydrogenase, ECG electro- cardiography
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