Ibrutinib-associated tumor lysis syndrome in chronic lymphocytic leukemia/small lymphocytic lymphoma and mantle cell lymphoma: A case series and review of the literature

Abstract

Background

Tumor lysis syndrome results when intracellular contents are released during cell lysis. Ibrutinib, a Bruton tyrosine kinase inhibitor, is used for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström’s macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Tumor lysis syndrome caused by ibrutinib therapy is potentially life threatening, but is rare and not often reported in clinical trials.

Objective

The purpose of this case series is to describe the occurrence of tumor lysis syndrome in two patients initiated on ibrutinib, and to highlight the importance of close monitoring during therapy.

Discussion

One patient with chronic lymphocytic leukemia/small lymphocytic lymphoma and one patient with mantle cell lymphoma developed laboratory and clinical tumor lysis syndrome following initiation of ibrutinib therapy. Assessment with the Naranjo Adverse Drug Reaction Probability Scale indicated one probable relationship and one possible relationship between ibrutinib therapy and tumor lysis syndrome. There were additional factors that may have confounded the laboratory and clinical factors observed, including baseline laboratory values and concurrent medications. Both patients were managed with supportive therapies. A literature review identified five additional reported cases of tumor lysis syndrome following ibrutinib therapy.

Conclusion

This case series identifies one patient with a probable relationship and one patient with a possible relationship between the development of tumor lysis syndrome and treatment with ibrutinib. Although uncommon, proper attention should be given to monitoring for this adverse drug reaction and appropriate follow-up should occur despite ibrutinib’s ease of administration.

Keywords

Bruton tyrosine kinase inhibitor medication safety ibrutinib tumor lysis syndrome

Introduction

Tumor lysis syndrome (TLS) results when intracellular contents such as purines and electrolytes are released during cell lysis, either spontaneously or in response to pharmacologic therapies that result in cell death.¹ It is most often a complication of hematologic malignancies such as acute leukemia or non-Hodgkin’s lymphomas, or their treatment. TLS occurs less frequently in indolent malignancies such as CLL, with an incidence reported at <1% after treatment with the chemotherapeutic agent fludarabine.² When TLS occurs, it can result in laboratory abnormalities including hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia. The Cairo–Bishop criteria classify this as laboratory TLS, and Table 1 describes criteria necessary to qualify for this classification. Additionally, other clinical manifestations such as nausea, vomiting, decreased renal function, cardiac arrhythmias, and seizures are possible and can be life-threatening. The development of clinical TLS has been associated with increased rates of death, and is classified via Cairo–Bishop criteria based upon presentation with laboratory TLS in addition to clinical signs or symptoms such as elevated serum creatinine, cardiac arrhythmias, or seizures.¹

Table 1.

Cairo–Bishop classification of laboratory tumor lysis syndrome in adults.¹

Laboratory measure	Value	Change from baseline^a
Uric acid	≥8 mg/dl	25% increase
Potassium	≥6 mg/dl	25% increase
Phosphorus	≥1.45 mmol/l or 4.5 mg/dl	25% increase
Calcium	≤1.75 mmol/l or 7.0 mg/dl	25% decrease

Changes in two or more laboratory values within three days before or seven days after cytotoxic therapy are required for diagnosis of laboratory tumor lysis syndrome.

Due to the potential severity of TLS complications, prophylaxis for TLS should be considered in patients being treated for certain malignancies. Determination of prophylaxis strategy is based on presence of risk factors such as type of malignancy, degree of tumor burden, rate of cellular proliferation, and sensitivity of the disease to chemotherapy. Evidence-based TLS guidelines provide criteria for classifying the risk of TLS into low-, intermediate-, or high-risk categories.¹ Allopurinol is a xanthine-oxidase inhibitor which inhibits the conversion of hypoxanthine and xanthine to uric acid which is renally excreted. Allopurinol, in combination with hydration, is the first-line therapeutic option in the prevention of hyperuricemia in patients who are at intermediate risk for TLS. High-risk patients should receive hydration and rasburicase, a recombinant form of urate oxidase that converts uric acid into allantoin, which is more soluble and more easily excreted in the urine. Rasburicase provides an advantage in patients where uric acid has already been formed or where hypoxanthine burden may be too high for allopurinol to effectively inhibit conversion to uric acid. For patients at low risk for TLS, the “watch-and-wait” approach is recommended with close monitoring, but allopurinol may be appropriate for this risk group and clinical judgment should be used when determining prophylaxis strategy.¹ Importantly, these prophylaxis strategies were initially developed for use with traditional cyclic chemotherapy, and it is unknown if these strategies are equally effective when used with chronic oral antineoplastic therapy.

Ibrutinib is an antineoplastic agent approved by the United States Food and Drug Administration for the treatment of certain hematologic malignancies including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia, mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL).³ It is the first in a relatively new class of Bruton Tyrosine Kinase inhibitors and is considered to be an important breakthrough in the treatment of CLL and MCL due to improved response rates, progression-free survival, and overall survival in both CLL/SLL and MCL.^4–9 Additionally, it is the first drug to gain FDA approval specifically for MZL, a malignancy with no standard treatment.¹⁰ In addition, ibrutinib has the advantage of being available as an oral dosage form, allowing patients to take the medication on an outpatient basis rather than in an infusion clinic. Like all pharmacologic therapies, however, treatment with ibrutinib can result in adverse events and its use requires careful patient selection and monitoring.

Commonly reported adverse effects of ibrutinib include lymphocytosis and hyperuricemia, but TLS is rare and not often reported in clinical trials.^5,8 Currently, few cases describing ibrutinib-induced TLS have been published in the scientific literature.^4,11,12,15 The purpose of this case series is to describe the occurrence of laboratory and clinical TLS in two patients initiated on ibrutinib for the treatment of CLL/SLL and MCL, and to highlight the importance of close monitoring during and after the initiation of therapy.

Patient presentation/discussion

Patient 1 is a 68-year-old African American male with Rai stage II CLL/SLL. Additional relevant past medical history includes stage III chronic kidney disease and a history of prostate cancer receiving androgen deprivation therapy. His Eastern Cooperative Oncology Group (ECOG) performance status at this time was 1.¹³ Prior CLL/SLL treatment included six cycles of pentostatin, cyclophosphamide, and rituximab, 400 cGy radiation of the bilateral axilla, and four cycles of bendamustine/rituximab. This resulted in the patient developing worsening renal insufficiency and neutropenia and ultimately led to the discontinuation of bendmustine/rituximab. Two months after discontinuation, the patient developed increasing axillary lymphadenopathy, abdominal girth, and lower extremity swelling consistent with disease progression. Initiation of ibrutinib was planned if renal function and hyperkalemia returned to levels supportive of safe treatment. Forty-one days prior to ibrutinib therapy, the patient developed hyperkalemia and was started on sodium polystyrene sulfonate suspension 15 g daily. After one month of observation, creatinine clearance was not adequate for ibrutinib or other chemotherapy treatment, so weekly rituximab 375 mg/m² was given two weeks and one week prior to ibrutinib initiation. The patient also concomitantly received allopurinol 100 mg daily for tumor lysis prophylaxis. Baseline labs one week prior to ibrutinib initiation included white blood cell count (WBC) 8400 cells/mm³ (normal 3700–9600 cells/mm³), creatinine 1.9 mg/dl (normal 0.6–1.4 mg/dl), potassium 4.3 mmol/l (normal 3.5–5.4 mmol/l), phosphorus 3.1 mg/dl (normal 2.4–4.7 mg/dl), uric acid 7.8 mg/dl (normal 2.5–7.9 mg/dl), and calcium 8.6 mg/dl (normal 8.5–10.1 mg/dl). A summary of the patient presentation is included in Table 2.

Table 2.

Summary of patient presentation with tumor lysis syndrome.

Patient	Ibrutinib treatment regimen	TLS risk category	Baseline labs	Patient labs at diagnosis of TLS	Intervention
1	420 mg daily	Low	WBC: 8400 cells/mm³ Scr: 1.9 mg/dl K⁺: 4.3 mmol/l Phos: 3.1 mg/dl UA: 7.8 mg/dl Ca⁺⁺: 8.6 mg/dl	WBC: 111,800 cells/mm³ Scr: 1.9 mg/dl K⁺: 5.3 mmol/l (day 3)^a Phos: 4.0 mg/dl (day 7)^a UA: 8.2 mg/dl^a Ca⁺⁺: 9.0 mg/dl	Oral fluid intake and IV fluids Adjusted sodium polystyrene Allopurinol 100 mg daily
2	280 mg daily	Low	WBC: 3900 cells/mm³ Scr: 1.1 mg/dl K⁺: 4.1 mmol/l Phos: not available UA: 3.7 mg/dl Ca⁺⁺: 8.3 mg/dl	WBC: 6.4 cells/mm³ Scr: 1.57 mg/dl K⁺: 5.3 mmol/l (day 7)^a Phos: 4.3 mg/dl UA: 5.1 mg/dl (day 7)^a Ca⁺⁺: 8.7 mg/dl	Oral fluid intake Decrease/discontinue oral potassium supplementation Allopurinol 450 mg total daily dose

Qualifying lab for laboratory tumor lysis syndrome.

WBC: white blood cell count; Scr: serum creatinine; K⁺: serum potassium; Phos: serum phosphorus; UA: serum uric acid; Ca⁺⁺: serum calcium.

Ibrutinib 420 mg daily was started and allopurinol 100 mg daily was continued along with sodium polystyrene 15 g daily. Patient remained Rai Stage II at the time of treatment. The first two doses of ibrutinib were administered on an inpatient basis to allow for close tumor lysis monitoring, but on the second day of therapy, labs remained stable except for a decrease in calcium to 8.0 mg/dl. The patient was discharged and weekly labs were subsequently monitored on an outpatient basis.

On day 7, labs were obtained revealing creatinine of 1.9 mg/dl, potassium 4.5 mmol/l, phosphorus 4.0 mg/dl (29% increase), and uric acid 8.2 mg/dl despite patient-reported adherence with allopurinol. The patient also reported compliance with ibrutinib, but stated that only one dose of sodium polystyrene was taken in the week prior. Since patient’s potassium remained within normal range with only one dose of sodium polystyrene 15 g, the medication was held at this visit. Additionally, the patient received 2 liters intravenous 0.9% sodium chloride due to elevated uric acid and phosphorus.

Labs on day 9 revealed creatinine 1.7 mg/dl, uric acid 7.7 mg/dl, and potassium 5.3 mmol/l which represented a 23% increase from baseline potassium. Phosphorus level was not available. Sodium polystyrene 15 g daily was reinitiated. On day 16, labs revealed potassium of 4.0 mmol/l, phosphorus of 3.1 mg/dl, and uric acid 8.7 mg/dl. At that time, the patient reported adherence to ibrutinib and sodium polystyrene, but noted two missed doses of allopurinol. Due to uric acid increase, allopurinol dose was increased to 200 mg daily and the patient was encouraged to maintain adequate oral fluid intake. Finally, on day 22 creatinine was 1.6 mg/dl and uric acid decreased to 7.6 mg/dl, but potassium increased to 4.7 mmol/l. Ibrutinib was continued along with allopurinol, sodium polystyrene, and adequate oral fluid intake.

Patient 2 is a 74-year-old Caucasian male diagnosed with MCL. Other relevant past medical history includes gout and a history of squamous cell carcinoma. His ECOG performance status was 1.¹³ His MCL was previously treated with six cycles bendamustine and rituximab complicated by grade 3 infusion reaction during the first rituximab infusion. This required administration of epinephrine and resulted in rituximab being held during cycle 1 only. The patient received the sixth cycle of bendamustine/rituximab six months after diagnosis, and subsequently received one cycle of maintenance rituximab 375 mg/m² planned for every two months. He presented to his primary care physician nine days before the second planned cycle of maintenance rituximab with painful bulky lymphadenopathy in bilateral inguinal nodes. Positron emission tomography scans showed bulky lymphadenopathy in the groin, chest, peritoneum, axilla, and left upper extremity. A Ki-67 immunohistochemistry stain showed overall proliferation rate of 60–70% consistent with transformation to the blastoid variant of MCL, a more aggressive form of the disease. The patient underwent excisional lymph node biopsy and ibrutinib was recommended. Eight days prior to ibrutinib initiation, the patient was admitted for surgical site infection and developed acute kidney injury which resolved. Abdominal wound and wound abscess cultures revealed s. aureus that was susceptible to clindamycin, erythromycin, sulfamethoxazole/trimethoprim (SMX-TMP), tetracycline, and rifampin. Negative pressure wound therapy was placed and he was discharged five days prior to ibrutinib initiation on a two week course of sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily for surgical site infection.

Baseline labs five days prior to ibrutinib initiation (day 1 of antibiotic course) included WBC 3900 cells/mm³, creatinine 1.1 mg/dl, potassium 4.1 mmol/l, and calcium 8.3 mg/dl. Phosphorus and uric acid values were not available within a relevant timeframe, and most recent uric acid available was 3.7 mg/dl three months prior to therapy initiation. The patient started ibrutinib, which coincided with day 5 of his antibiotic course. Due to recent infection and acute renal injury, ibrutinib was initiated at a reduced dose of 280 mg daily with a goal of titrating to 560 mg daily. The patient was already taking allopurinol 300 mg daily for gout and this was continued. Additionally, the patient had a history of hypokalemia and was taking potassium chloride, but the dose was decreased from 20 mEq daily to 10 mEq daily given the potential for TLS. The patient was then seen in clinic on day 2 of ibrutinib therapy and his creatinine had risen to 1.6 mg/dl (45% increase) and potassium rose to 4.9 mmol/l (20% increase). Uric acid level was not available at this time. Sulfamethoxazole/trimethoprim (ibrutinib day 2/antibiotic day 7) was continued, but potassium chloride was held. Allopurinol was increased to 300 mg every morning and 150 mg every evening. On day 7 of ibrutinib (antibiotic day 11), creatinine remained stable at 1.6 mg/dl but potassium had risen to 5.3 mmol/l (29% increase from baseline) and uric acid had risen to 5.1 mg/dl (38% increase from most recent value). Oral fluid intake was encouraged and allopurinol was continued. On day 28 (20 days after SMX/TMP completion), creatinine dropped to 1.1 mg/dl and potassium was 3.8 mmol/l. Ibrutinib dose was increased to 420 mg daily. Labs from day 42 revealed creatinine 1.3 mg/dl, potassium 4.1 mmol/l, and calcium 8.1 mg/dl. WBC was 11,500 cells/mm³ consistent with lymphocytosis expected with ibrutinib therapy.

This case series identifies two patients who developed laboratory and clinical TLS while taking ibrutinib for CLL/SLL and MCL despite prophylactic measures with allopurinol. Use of the Naranjo Adverse Drug Reaction Probability Scale indicates a probable relationship between TLS and ibrutinib use for Patient 1, and a possible relationship for Patient 2 (Table 3).¹⁴ Patient 1 had elevated potassium prior to ibrutinib initiation and the cause of hyperkalemia following ibrutinib initiation may have due to tumor lysis syndrome or pre-existing hyperkalemia. However, he still met Cairo–Bishop criteria for laboratory TLS based on elevated phosphate and uric acid levels alone which would not have been influenced by elevated potassium or other potential causes. Additionally, the patient experienced a 23% rise in potassium from baseline despite stable potassium in the week prior in the absence of sodium polystyrene. The patient also met criteria for clinical TLS due to creatinine elevation requiring intravenous fluid administration. Of note, the laboratory abnormalities occurred on different days, which could signal other potential causes; however, there were no identified factors likely to cause isolated hyperuricemia or hyperphosphatemia.

Table 3.

Naranjo adverse drug reaction probability scale (adapted from Naranjo et al.¹⁴).

Criteria	Patient 1	Patient 2
1. Has conclusive evidence of this adverse drug reaction been reported previously?	+1	+1
2. Did the appearance of the adverse event occur after administration of the suspected drug?	+2	+2
3. Was improvement documented after the drug was discontinued?	+1	+1
4. Did the adverse reaction reoccur when rechallenged with the drug?	0	0
5. Could the adverse reaction have resulted from an alternative cause?	0	−1
6. Did the adverse reaction reoccur when administered a placebo?	0	0
7. Were laboratory drug levels able to validate the toxicity?	0	0
8. Was the reaction dose dependent, increasing in severity with increasing dose?	0	0
9. Did a previous exposure result in a similar adverse reaction in this patient?	0	0
10. Was objective evidence used to confirm this adverse reaction?	+1	+1
Total score	5^a	4^a

Total score of ≥9 = definite; 5–8 = probable; 1–4 = possible; ≤ 0 = doubtful.

Patient 2 met Cairo–Bishop criteria based on potassium and uric acid elevations of greater than 25% from baseline, but it is possible that this patient’s hyperkalemia could have been caused, in whole or in part, by concurrent treatment with SMX/TMP which is known to cause both hyperkalemia and elevated serum creatinine. SMX/TMP use could also have resulted in competitive excretion with uric acid which, along with prior history of gout, may have been an additional contributor to the patient’s hyperuricemia. However, laboratory abnormalities continued to be seen following completion of SMX/TMP therapy, which suggests the possibility of alternative causes for the laboratory changes, including tumor lysis syndrome caused by ibrutinib. Additionally, Patient 2’s renal function worsened during the first weeks of ibrutinib therapy which may have impacted allopurinol clearance and subsequently uric acid levels. Since allopurinol is renally cleared, the daily dose of 450 mg was likely functionally higher during the period of acute renal dysfunction. Thus, it is possible that his uric acid level would have been further elevated had renal dysfunction not contributed to decreased clearance, and subsequently increased functional activity, of allopurinol.

The two identified patients experienced laboratory abnormalities within one week of ibrutinib initiation, supporting a rapid development of TLS. This is important since patients may not be followed weekly by their primary oncology provider, especially if they are taking oral therapies not requiring administration as an inpatient or in clinic. It is also important to consider the baseline risk for development of TLS and prophylactic strategies that are used, as both patients in this case series developed TLS despite being on prophylactic therapy appropriate for their risk factors. The potential for life-threatening events occurring before a regularly-scheduled follow-up visit highlights the importance of close follow-up for patients taking ibrutinib regardless of baseline risk or use of prophylactic measures.¹ More frequent laboratory measurements may be necessary during early phases of therapy to ensure patients do not require medical management of TLS, especially those with comorbidities that may predispose them to higher risks of renal dysfunction or electrolyte abnormalities.

Limitations

While this case series supports the probability of TLS occurring in patients taking ibrutinib, it was only able to describe the development of TLS in two patients. There were also confounding factors present in each patient case which may have contributed to the laboratory and clinical abnormalities seen, including concurrent medications and baseline renal dysfunction. Additionally, as close laboratory monitoring and medical management prevented worsening TLS in these patients, it is unknown if a lack of close monitoring would have resulted in significant clinical complications. It is important that healthcare professionals continue to report adverse events in order to gain a better understanding of clinical implications as well as need for monitoring.

Literature review

A literature review was conducted by searching Medline (1956 to February 2017) and Embase (1957 to February 2017) using the search terms ibrutinib and tumor lysis syndrome. The preliminary search identified 35 publications, and the titles and abstracts of these publications were reviewed for relevance. Reference lists of included articles were also manually searched for additional relevant publications.

A total of five potential cases involving tumor lysis syndrome during ibrutinib monotherapy were identified.^4,10,12,15 The first described a 57-year-old male diagnosed with Rai stage II CLL. The patient received ibrutinib 420 mg daily and within seven days of initiation developed weakness, fatigue, elevated body temperature, hypotension, bradycardia, and tachypnea. Laboratory results revealed significant elevations in serum potassium, creatinine, phosphate, and uric acid as well as decreased serum calcium. The patient required admission to the intensive care unit for management of TLS with intravenous fluids, bicarbonate drip, calcium infusion, insulin, dextrose 50% in water, sodium-polystyrene, and rasburicase.¹⁰ Additionally, a phase 1b/2 study which included 84 patients who received ibrutinib 420 mg daily or 840 mg daily identified one patient who developed severe TLS.⁴ A phase II registration study reported two patients who were determined to have developed laboratory TLS during ibrutinib therapy, occurring after one and two months of treatment.¹² Finally, a 75-year-old male with Ann Arbor Stave IVB MCL who was taking ibrutinib 560 mg daily developed laboratory and clinical TLS including sinus tachycardia and acute renal failure, which required hospital admission and treatment with intravenous saline and rasburicase.¹⁵

Similar to the patients presented in this case series, the literature search identified patients with CLL/SLL, as well as MCL, who developed TLS during ibrutinib therapy. Additionally, all patients had either an intermediate or low risk for developing TLS.^1,4,10,12 These reported cases provide evidence to support the potential for TLS occurrence in patients receiving ibrutinib in multiple malignancy types regardless of baseline TLS risk category.

Although the incidence of TLS remains low in patients taking ibrutinib, the result of such events has the potential to be life-threatening. It is important to note that TLS is a constellation of symptoms which may be reported individually in clinical trials rather than as the named syndrome, thus potentially underestimating the prevalence of TLS seen in clinical trials. Clinical implementation of ibrutinib use still requires laboratory monitoring during treatment initiation despite its use in an outpatient setting. High-risk patients using ibrutinib, or any oral chemotherapy agent, should be monitored closely for TLS and other adverse events to ensure patient safety, and similar close monitoring should be considered for patients at low or intermediate risk. Patient education is also important to ensure the patient understands and appreciates the need for adherence to ibrutinib and concurrent therapies, follow-up, and monitoring recommendations.

Conclusion

Tumor lysis syndrome is reported to be rare in patients taking ibrutinib, but this case series and review of previously published literature identified seven patients who developed TLS after ibrutinib initiation. Proper attention should be given to monitoring this oral chemotherapy treatment, and patient-specific characteristics should be considered when determining an individual’s risk for adverse events. Additionally, appropriate follow-up should not be omitted due to the ease of administration of the drug.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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