Successful use of blinatumomab in a patient with acute lymphoblastic leukemia and severe hepatic dysfunction

Background

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy characterized by the proliferation of lymphoblasts (B- or T-cell origin) in the bone marrow, blood, and/or tissues. It is estimated that 5960 new cases of ALL and 1470 deaths will occur in 2018. ¹ The incidence of ALL is significantly higher in pediatric patients, with over 55% of cases occurring in individuals <20 years of age. ² Although the incidence is higher, treatment outcomes for childhood ALL are considerably more favorable than adult ALL. A 95% complete remission (CR) rate and an overall survival (OS) rate exceeding 80% is seen in childhood ALL, while adult CR and OS rates are 80%–90% and 30%–50%, respectively.^3–6

The inferior outcomes in older adults are thought to be mediated by various disease-related and patient-related factors, including, but not limited to, a higher proportion of poor risk cytogenetics, Ph + ALL, Ph-like ALL, as well as a higher rate of medical comorbidities and poor tolerance to chemotherapy.^3,7–12 Data in adolescent and young adult patients demonstrate promising clinical outcomes in those receiving more-intensive pediatric-inspired regimens that place a greater emphasis on asparaginase therapy.^13–19 Unfortunately, adult patients often experience significant toxicities with asparaginase, in particular, life-threatening hepatotoxicity. ²⁰ In those that develop hepatotoxicity from asparaginase in ALL inductions, 30-day mortality is high, and this often leads to inability to deliver consolidation and/or reinduction therapy in those that do not achieve remission. Establishing effective treatment options in patients with hepatic dysfunction will become increasingly more important as the aggressive use of asparaginase in adult patients continues to rise.

Blinatumomab, a novel bispecific T-cell engager (BiTE), has shown promising results in the treatment of R/R B cell ALL, significantly improving CR rates and OS rates over other Food and Drug Administration (FDA)-approved therapies.^21–27 Hepatic impairment is expected to have limited effect on clearance of blinatumomab, since blinatumomab is a therapeutic protein that does not undergo hepatic metabolism. However, no data exist on the safe use of blinatumomab in significant hepatic dysfunction, as these patients were excluded from the clinical trials. Here, we report a case demonstrating the safe and effective use of blinatumomab reinduction in an older adult patient with refractory Ph-like ALL in the setting of significant hepatic dysfunction secondary to induction therapy and progressive ALL.

Case report

A 66-year-old obese female (weight: 84.1 kg, height: 152.4 cm, body surface area: 1.89 m²) presented to the Michigan Medicine Emergency Department with a new diagnosis of B Cell ALL. Labs on admission revealed a white blood cell count of 14 K/µL (80% blasts), a hemoglobin of 6.7 g/dL, and platelets of 45 K/µL. Flow cytometry was consistent with a diagnosis of B lymphoblastic leukemia. The patient had no evidence of cirrhosis or chronic liver disease on history or labs (baseline total bilirubin 0.2 mg/dL). Fluorescence in situ hybridization revealed a CRLF2 rearrangement but no evidence for the BCR/ABL1 gene fusion or MLL rearrangement, consistent with Ph-like ALL. Conventional cytogenetics revealed no additional genetic abnormalities (46,XX [20]), and cytogenetic array demonstrated losses of IKZF1 and PAX5, consistent with an “Ikaros Plus” classification. ²⁸ Other notable mutations included JAK2 (33%) and NRAS (27%).

She initiated induction chemotherapy with a modified Larson regimen ²⁹ (two rituximab doses were added given CD20 + disease, and pegaspargase was dose reduced to 1000 IU/m² as is standard practice at our institution for elderly patients and moved to day 15 to mitigate hepatotoxicity risk) in April 2018. Her post-induction course was complicated by polymicrobial gram-negative sepsis and nasal vestibulitis. She was discharged home on day 20 following resolution of acute issues and peripheral blood count recovery. However, she was subsequently re-admitted with multiple issues including micrococcus bacteremia (possible contaminant), segmental pulmonary embolism with right ventricular strain, mild pancreatitis, splenic vein thrombosis, supraventricular tachycardia, and hyperbilirubinemia.

The hyperbilirubinemia and liver function test (LFT) elevations were presumed to be caused by pegaspargase drug-induced liver injury (DILI). LFT elevation started within 10 days after pegaspargase administration. She had normal factor V levels, and no evidence of cirrhosis or chronic liver disease on history or labs. A right upper quadrant ultrasound with Doppler was non-revealing and a magnetic resonance imaging (MRI) demonstrated severe hepatic steatosis with scattered parenchymal inflammation. No biliary ductal dilatation or evidence of infection was seen on computed tomography or MRI of the abdomen/pelvis. A liver biopsy showed steatosis with steatohepatitis and canalicular cholestasis, with no evidence of an immune process, consistent with DILI secondary to pegaspargase. The patient was treated with levocarnitine (intravenous initially, then post-operative oral) and ursodiol for hepatic dysfunction and enoxaparin for thrombosis. Despite levocarnitine and ursodiol use, LFTs continued to rise over the next few weeks (max total bilirubin 20.6 mg/dL, direct bilirubin 15.9 mg/dL, indirect bilirubin 4.7 mg/dL, aspartate aminotransferase (AST) 238 IU/L, and alanine aminotransferase (ALT) 182 IU/L).

A post-induction bone marrow biopsy on day 27 revealed persistent disease (20% blasts). Based on her continued severe hepatic dysfunction, poor tolerance with induction cytotoxic chemotherapy, and low bone marrow blast percentage, the decision was made to initiate blinatumomab for refractory disease. The dosing of blinatumomab followed the FDA-approved label (9 mcg/day on days 1–7, 28 mcg/day on days 8–28). ³⁰ After initiation, the patient's liver enzymes improved at first, but then began to worsen (total bilirubin from 17.6 mg/dL to 27.50 mg/dL). The decision was made to continue blinatumomab including dose escalation. She tolerated the dose escalation well and liver enzymes began to improve, returning to <2.0 mg/dL on day 77 (Figure 1).

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Figure 1.

LFT trend following R-Larson induction.

She underwent restaging bone marrow biopsy on day 37 of cycle 1 of blinatumomab which revealed a morphologic CR, with negative minimal residual disease (MRD) by flow cytometry. She proceeded with blinatumomab cycle 2 on day 82 while undergoing allogeneic hematopoietic cell transplant (alloHCT) work-up. Restaging bone marrow biopsy prior to planned admission for transplant was done on day 56 of cycle 2 of blinatumomab and revealed no morphological evidence of ALL; however, MRD assessment noted 0.061% phenotypically abnormal B cells. The patient successfully proceeded to an allogeneic hematopoietic cell transplant without complication.

Discussion

To our knowledge, this is the first reported case demonstrating the safe and effective use of blinatumomab in a patient with severe hepatic dysfunction. The blinatumomab prescribing information makes no recommendations for the initiation of blinatumomab in patients with hepatic dysfunction, although there is a recommendation to interrupt treatment if transaminases rise to >5 times the upper limit of normal (ULN) or if bilirubin rises to >3 times the ULN. ³⁰ Furthermore, patients with severe hepatic dysfunction have been excluded from all pivotal trials involving blinatumomab.^21–27 Given the paucity of data to support the use of nearly all standard of care treatment regimens in the setting of hepatic dysfunction, clinicians are left with a challenging decision.

Relapsed/refractory (R/R) ALL carries an extremely poor prognosis, especially in elderly adult patients. OS at 5 years after relapse remains low at 7%, suggesting that most adults with R/R ALL cannot be cured by conventional treatment. ³¹ Patients who achieve a CR with salvage therapy may be eligible for hematopoietic stem cell transplant, although cure rates remain low at 10%–30%. ³² Conventional treatment with salvage chemotherapy for R/R Ph− ALL frequently mirrors variations of drug combinations used in induction protocols. Combinations of vincristine, steroids, anthracyclines, asparaginase and methotrexate, and nucleoside analogues are frequently used with CR rates between 17% and 83%. ³³

Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) Part B is frequently used at our institution for R/R ALL following failure of BFM-based regimens (e.g., Larson, CALGB10403). Strong consideration was given to initiate the patient on Hyper-CVAD B following discovery of persistent disease. Unfortunately, methotrexate is not recommended in patients with total bilirubin >5.0 mg/dL, and limited guidance exists for cytarabine dose adjustments in patients with severe hepatic dysfunction. Administration of 50% of the recommended cytarabine dose has been recommended with dose escalation in the absence of toxicity, but there are virtually no data to support these recommendations.^34,35 Lack of substantial evidence to support such a dose reduction, the patients performance status, her advanced age, and her poor tolerance to prior induction chemotherapy ultimately led us to determine that it was not in the best interest of our patient to pursue salvage chemotherapy with Hyper-CVAD B.

Like Hyper-CVAD B, few standard of care treatment options have well-supported dose adjustment recommendations for patients with hepatic dysfunction. Mild-moderate hepatic dysfunction can often be managed with empiric dose adjustments of chemotherapy agents. In our patient with fulminant hepatic dysfunction with Common Terminology Criteria for Adverse Event grade 4 serum bilirubin elevation and grade 3 AST and ALT elevations, ³⁶ options were very limited. Beyond salvage chemotherapy, National Comprehensive Cancer Network guidelines recommend consideration for a clinical trial, blinatumomab (category 1), inotuzumab ozogamicin (category 1), or tisagenlecleucel (patients < 26 year) in addition to chemotherapy for R/R Ph− ALL. ³⁷ New clinical trials frequently exclude patients with hepatic dysfunction and inotuzumab ozogamicin is associated with severe hepatotoxicity, including sinusoidal obstruction syndrome. ³⁸ Tisagenlecleucel therapy takes several weeks to manufacture which would have delayed reinduction significantly, is associated with severe cytokine release syndrome (CRS) which can cause multiorgan failure including liver failure, has not been studied in patients with significant organ dysfunction, and cost and insurance issues are major barriers to use. Thus, blinatumomab was felt to be the best option for our patient in this setting.

Blinatumomab is a BiTE antibody construct that links CD19-positive B cells to CD3-positive T cells, resulting in induction of T-cell-mediated serial lysis of B cells and concomitant T-cell proliferation. ³⁹ Blinatumomab represents a significant breakthrough in R/R B cell ALL, demonstrating a CR/CRi rate of 43% of patients within the first two cycles of treatment in a large phase II study of patients with R/R Ph− B cell ALL.^23,24 In a follow-up prospective, multicenter, randomized, phase III trial in patients with R/R B cell precursor ALL, blinatumomab demonstrated longer OS versus standard re-induction chemotherapy (7.7 vs. 4.0 months, P = 0.011) and higher remission rates (CR, 34% vs. 16%; P < .001). ²⁵ In both studies, remission rates were even higher among patients with <50% blasts at the time of treatment (CR, 65.5%–73%), as was the case in our patient.^23,25 Thus, blinatumomab displays excellent single-agent activity and may serve as a successful bridge to allogeneic hematopoietic cell transplantation.

No formal pharmacokinetic studies have been conducted on blinatumomab in patients with hepatic impairment. As a therapeutic protein that does not undergo hepatic metabolism, hepatic impairment is expected to have little effect on the clearance of blinatumomab, which has been confirmed in at least one study. ³⁹ However, treatment with blinatumomab has been associated with transient elevations in liver enzymes in some studies. ⁴⁰ The majority of these events are thought to be due to CRS and inflammation-induced liver injury. Although CRS and resulting transient liver injury can occur with blinatumomab, grade 3/4 CRS events are rare (2%–4.9%). Given the short half-life of blinatumomab, in the case of severe CRS or hepatic injury, stopping the infusion and administration of steroids results in rapid improvement of such cases, as has been shown previously. ⁴¹

In our case, diligent monitoring of vitals, C-reactive protein, ferritin, lactic acid, LFTs, and international normalized ratio was undergone to intervene early and prevent any potential CRS-induced worsening of hepatic function. This allowed careful administration of blinatumomab, without dose modification, despite a total bilirubin of 20.6 mg/dL. Following initiation, the patient's LFTs improved initially, then began to worsen slightly with the bilirubin rising to 27.5 mg/dL. It was unclear whether the increase in bilirubin was secondary to blinatumomab or continued bilirubin elevation from pegaspargase, as peak LFT elevations following pegaspargase administration can be delayed for several weeks. ⁴¹ Given this uncertainty, lack of concomitant CRS, the patient's relapse history with poor prognosis, and limited therapeutic options, the decision was made to continue blinatumomab following the normal dosing and dose escalation scheme. Fortunately, the patient tolerated the dose escalation well, and liver enzymes began to improve and eventually returned to <2.0 mg/dL on day 77 (63 days after pegaspargase administration). Cycle 2 of blinatumomab was also well-tolerated.

Patients with ALL and significant hepatic dysfunction have an extremely poor prognosis, as most chemotherapeutic agents are either unsafe or have not been studied in this setting. ⁴¹ Our case demonstrates that blinatumomab is a viable option for the treatment of R/R ALL patients with severe hepatic impairment. We were able to successfully administer this agent without dose adjustment, thus allowing our patient to achieve a CR and proceed to potentially curative alloHCT without untoward side effects. With limited other options in this setting of R/R ALL and significant hepatic dysfunction, it is valuable knowledge that blinatumomab may be safely and effectively utilized. Further, larger studies are warranted examining pharmacokinetics of blinatumomab in those with organ dysfunction to help confirm the optimal dose and disposition of this critical agent.