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. Author manuscript; available in PMC: 2019 Aug 9.
Published in final edited form as: Clin J Oncol Nurs. 2019 Jun 1;23(3):E52–E59. doi: 10.1188/19.CJON.E52-E59

Moxetumomab pasudotox: clinical experience in relapsed/refractory hairy cell leukemia

Julie Feurtado 1, Robert J Kreitman 1
PMCID: PMC6688475  NIHMSID: NIHMS1044557  PMID: 31099793

Abstract

BACKGROUND:

Moxetumomab pasudotox is a promising new therapy for the treatment of patients with relapsed/refractory hairy cell leukemia (R/R HCL), but practical guidance relating to its administration is limited.

OBJECTIVES:

To describe the authors’ experience of administering moxetumomab pasudotox to patients with R/R HCL in the clinic.

METHODS:

Considerations pertaining to administration of therapy and suggestions for patient monitoring are outlined, and case studies are presented.

FINDINGS:

Nurses play a pivotal role in the management of patients who are receiving moxetumomab pasudotox. Monitoring of clinical and laboratory parameters before, during and after administration of moxetumomab pasudotox are key to assessing treatment responses and to detecting signs of serious side effects. Patients should be educated as to the importance of remaining well hydrated during treatment and on the symptoms of common and serious side effects of moxetumomab pasudotox. Nurses are also well placed to address and alleviate common concerns that patients express in relation to their treatment.

The approaches for patient care outlined in this review can be applied to other institutions planning to use moxetumomab pasudotox for the treatment of patients with R/R HCL.

Keywords: hairy cell leukemia, moxetumomab pasudotox, novel therapies, immunoconjugates

Overview of HCL and its treatment

Hairy cell leukemia (HCL), a chronic mature B-cell malignancy, accounts for approximately 2% of all leukemias, with an estimated 1200 new cases occurring in the USA each year (Kreitman & Arons, 2018). In common with other B-cell malignancies, patients with HCL often present with symptoms of fatigue and infection or bleeding, and may also have abdominal fullness owing to splenomegaly (Chang, Stroup, & Weiss, 1992; Wanko & de Castro, 2006). A definitive diagnosis of HCL can be made through recognition of its characteristic immunophenotype: hairy cells express several cell surface markers at high levels, including CD19, CD20, CD22, CD11c and CD25 (Stetler-Stevenson & Tembhare, 2011; Thompson & Ravandi, 2017). Classical HCL is immunophenotypically and genetically distinguishable from other HCL-like disorders, which include HCL variant and splenic diffuse red pulp lymphoma (Troussard & Cornet, 2017).

The current treatment paradigm for HCL is based on the clinical evaluation of patients. Classical HCL has an indolent disease course and asymptomatic patients with acceptable blood counts are managed with a ‘watch and wait’ strategy (Golomb, 1983). For the majority of patients who present with disease symptoms or low complete blood cell counts, first-line therapy generally comprises purine nucleotide analogues (PNAs), typically, cladribine or pentostatin (Jones et al., 2012; Robak, Matutes, Catovsky, Zinzani, & Buske, 2015). Although these therapies produce high rates of complete response (Else et al., 2009; Rosenberg, Burian, Waalen, & Saven, 2014), patients often have remaining minimal residual disease (MRD), which frequently results in disease relapse (Kreitman & Arons, 2018).

Choice of second- and subsequent-line therapies in patients who relapse depends on the duration of their first remission (Grever et al., 2017). Patients who relapse before 2 years of remission are often considered as relapsed/refractory (R/R) patients, but even patients relapsing after longer intervals may be considered as R/R owing to the decreasing efficacy and increased cumulative myelotoxicity of chemotherapy with each course given. HCL in these patients can be ‘hard-to-treat’ owing to poor tolerance to chemotherapy, increased risk of infection and decreased responsiveness to chemotherapy (Jain, Polliack, & Ravandi, 2015; Maevis, Mey, Schmidt-Wolf, & Schmidt-Wolf, 2014).

In recent years, targeted therapies have shown efficacy in patients in whom therapy with pentostatin or cladribine has failed. The anti-cluster of differentiation-20 (CD20) monoclonal antibody rituximab, when combined with PNAs, has high and durable rates of complete remission (CR) in clinical studies (Else, Dearden, & Catovsky, 2015; Thompson & Ravandi, 2017). However, this treatment regimen is at least as toxic as, and perhaps more toxic than, repeated PNA therapy because the prolonged B-cell depletion and hypogammaglobulinemia after rituximab therapy adds to the immunodeficiency that patients experience with PNAs (Christou, Giardino, Worth, & Ladomenou, 2017; Sacco & Abraham, 2018). Treatment with BRAF inhibitors may also lead to CR in patients with R/R disease, but without clearance of MRD. Indeed, relapse is frequently reported within a median of less than 2 years post treatment in these patients (Tiacci et al., 2015). Other targeted therapies include Bruton tyrosine kinase (BTK) inhibitors and recombinant immunotoxins that target CD22 (Kreitman & Pastan, 2015; Troussard & Cornet, 2017).

Treatment strategies that achieve high rates of MRD eradication are desirable in R/R HCL owing to reports of a positive association between attainment of MRD negativity and the duration of disease remission (Park & Tallman, 2014). Monoclonal antibody-based approaches combining rituximab with a PNA have been reported to eliminate MRD in a high proportion of patients (Chihara et al., 2016; Lauria & Forconi, 2009; Ravandi, 2011). The remainder of this discussion will focus on moxetumomab pasudotox, a novel monoclonal antibody-based agent, that can achieve MRD in patients with R/R HCL without requiring the use of chemotherapy. Our recommendations, based on treatment at the National Institutes of Health (NIH) will be outlined.

Moxetumomab pasudotox

Moxetumomab pasudotox (HA22, CAT-8015) is a first in-class, novel, recombinant chimeric anti-CD22 immunotoxin that consists of the variable domain of a CD22 monoclonal antibody, fused to a fragment of pseudomonas exotoxin (Kreitman et al., 2011; Kreitman & Pastan, 2011, 2015). Moxetumomab pasudotox is not a chemical conjugate because the entire recombinant protein is produced in Escherichia coli (Salvatore, Beers, Margulies, Kreitman, & Pastan, 2002).

Moxetumomab pasudotox showed promising initial results in phase 1 studies of patients with R/R HCL, with CR rates of 64% and a longer median duration of CR in patients who achieved MRD negativity versus patients with MRD positive status (42.1 vs 13.5 months) (R. J. Kreitman et al., 2018). Recent results from a pivotal single-arm phase 3 study in 80 patients with R/R HCL demonstrated deep and durable responses in heavily pretreated patients with R/R HCL. Durable CR, defined as CR with resolution of cytopenias (hematologic remission [HR]) for at least 6 months, was achieved by 30% of patients, and 85% of patients who achieved CR had MRD negativity. Moxetumomab pasudotox had an acceptable safety profile; treatment-related serious adverse events of hemolytic uremic syndrome (HUS; 7.5%) and capillary leak syndrome (CLS; 5%) were reversible and manageable with supportive care and treatment discontinuation (Robert J. Kreitman et al., 2018). On the basis of these findings, moxetumomab pasudotox was approved by the Food and Drug Administration for the treatment of patients with HCL who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Additionally, the 2019 NCCN guidelines now include moxetumomab pasudotox as a third line therapy for patients with R/R disease (NCCN, 2019).

Considerations for nurses involved in the management of patients with HCL who are receiving treatment with moxetumomab pasudotox

Nurses play a central role in the care of patients with HCL in clinical practice, but key guidelines for the management of HCL (Grever et al., 2017; Robak et al., 2015) provide little advice on practical aspects of patient management. Moreover, as moxetumomab pasudotox is a new therapy, there is limited published guidance specific to its administration. Based on clinical experience of treating patients with moxetumomab pasudotox at the National Institutes of Health (NIH) and reported experiences of phase 3 clinical trials from healthcare professionals, suggestions for the management of patients receiving moxetumomab pasudotox for the treatment of R/R HCL are outlined below.

Considerations prior to administration of moxetumomab pasudotox

It is essential to obtain a baseline medical history prior to starting treatment with moxetumomab pasudotox. This should include details of past or current cardiovascular and/or kidney disease, recent or active infection and all concomitant medications. Comorbidities, such as chronic heart failure, chronic obstructive pulmonary disorder or renal disease, and contraindications should be considered because treatment could cause a flare of related symptoms. Reproductive status and plans for future pregnancy should also be discussed. The following tests are recommended: height and weight measurement, blood pressure measurement, blood tests to include complete blood count, differential and a comprehensive metabolic panel (Chem 20; chemistries), and urinalysis (see Table 1).

Table 1.

NURSE CHECKLIST FOR PRIOR TO, DURING AND POST ADMINISTRATION OF MOXETUMOMAB PASUDOTOX

graphic file with name nihms-1044557-t0004.jpg
graphic file with name nihms-1044557-t0005.jpg
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CLS, capillary leak syndrome; DEHP, di-(2-ethylhexyl) phthalate; HUS, hemolytic uremic syndrome; Hx, history; IV, intravenous; LDH, lactate dehydrogenase; PO, per oral; PVC, poly(vinyl chloride); ULN, upper limit of normal

Pre-treatment management

Hydration is of paramount importance when administering moxetumomab pasudotox because it can aid in preventing and managing CLS and HUS, as well as other adverse events. Patients should be educated regarding the importance of compliance with oral and intravenous hydration recommendations while receiving treatment, to prevent toxicity and premature cessation of treatment. Accordingly, patients are advised to avoid strenuous exercise, in order to prevent excessive fluid loss, and to monitor their fluid intake carefully. The use of non-steroidal anti-inflammatory drugs other than aspirin is not permitted owing to the potential for nephrotoxicity.

Hydration and premedication

Before and after each dose of moxetumomab pasudotox, patients are given one liter of intravenous fluid and for prevention of allergic side effects premedicated with hydroxyzine, acetaminophen and ranitidine. (see administration recommendations in Table 1). Administration of aspirin (81 mg daily) is recommended on days 1–8 to help prevent platelet aggregation, possibly a later step in HUS.

Administration of moxetumomab pasudotox and post-treatment management

Moxetumomab pasudotox is administered intravenously at a dose of 0.04 mg/kg over 30 minutes on days 1, 3, and 5 of every 28-day treatment cycle after prehydration with 1 L of fluid (Figure 1). Patients who weigh less than 50 kg (110 lbs) can receive 500 mL fluid rather than 1 L as pre and post hydration. Both moxetumomab pasudotox and hydrating fluids are administered on a pole-mounted volumetric infusion pump, as shown in Figure 2. Following treatment, administration of antihistamine and antipyretic medications, as well as a corticosteroid, should be considered, again, as directed (Table 1). Dexamethasone 4 mg orally was often highly effective in stopping nausea, headache and fever, although these symptoms would generally occur 6–12 hours after rather than during the infusion.

Figure 1.

Figure 1.

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TREATMENT REGIMEN FOR MOXETUMOMAB PASUDOTOX

Note: moxetumomab pasudotox is administered for a maximum of six treatment cycles

Figure 2.

Figure 2.

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DIRECTIONS FOR ADMINISTRATION OF MOXETUMOMAB PASUDOTOX

PIV, peripheral intravenous device; PICC, peripherally inserted central catheter

It is important for nurses to remember and verify that the dose of moxetumomab pasudotox is established on day 1, cycle 1 and should not change during therapy unless the patient’s weight changes by more than 10% during treatment. To this effect, it is important that patients’ weight is monitored regularly; both to ensure that the correct dose of moxetumomab pasudotox is administered and to monitor for side effects.

We recommend that patients drink up to a cup (8 oz or 240 mL)/hr of non-caffeinated fluids, including water, milk, juice or other non-alcoholic beverages, totalling up to 6 L in a 24 period during days 1–8 of treatment. Patients should be instructed to drink gradually, as leaking of fluid from the inside to the outside of blood vessels also occurs gradually, including while they are sleeping. For this reason, it is recommended that patients avoid going for more than 2–3 hours at night without drinking. Administering intravenous fluid more than the liter given before and after each dose of moxetumomab pasudotox may be associated with edema and pleural effusions, possibly owing in part to the salt content of the administered therapy. Since patients with weight gain may be intravascularly fluid depleted diuretics given prior to day 8 should be avoided unless patients experienced significant dyspnea, which itself canbe avoided by administering oral rather than excess intravenous fluid.

Advice for the management of side effects

Nurses play a key role in educating patients on the side effects and the importance of reporting them to their treatment team. Important side effects to monitor for include:

  • Cytokine release syndrome
    • More likely to occur during cycles 1 and 2 but could occur at any time
  • Capillary leak syndrome
    • May occur during any cycle; usually prior to day 8
  • Elevated liver enzymes
    • May occur during any cycle
  • Hemolytic uremic syndrome
    • May occur during any cycle and day of treatment

Table 3.

GUIDANCE FOR MONITORING PATIENTS FOR SIGNS OF HUS AND CLS

HUS CLS
Parameters to check  • Hemoglobin
 • Platelet count
 • Serum creatinine		  • Weight
 • Blood pressure
Signs and symptoms See Table 2 See Table 2
Consider a diagnosis if the following are present ≥ Grade 2 creatinine increase AND one of the following:
 • hemoglobin decreased by 1 g/dL
 • platelet count < 25 000/mm3 (unrelated to underlying disease)		 If weight has increased by ≥ 10% from day 1 of each cycle, and the patient is hypotensive, check for peripheral edema, hypoalbuminemia, and respiratory symptoms, including dyspnea and cough
If suspected, check the following Evidence of hemolysis:
 • blood LDH
 • indirect bilirubin
 • blood smear schistocytes		  • Decrease in oxygen saturation
 • Evidence of pulmonary edema
And/or
 • Serosal effusions
Suggested treatment Appropriate supportive measures, including fluid repletion and hemodynamic monitoring; hospitalization should be considered if clinically indicated Standard symptomatic treatment, including administration of concomitant corticosteroids (PO/IV); hospitalization as clinically indicated
Time to onset May occur during any cycle of treatment May occur during any cycle of treatment; usually before day 8
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CLS, capillary leak syndrome; HUS, hemolytic uremic syndrome; IV, intravenous; LDH, lactate dehydrogenase; PO, per oral

Symptoms suggesting delayed cytokine release include chills, muscle pain, and fever. Symptoms suggestive of CLS include mild swelling in the hands, feet, face, or ankles; nausea, dizziness, vomiting, headache, low blood pressure, and associated laboratory parameters, including low albumin levels in the blood and proteinuria (Tables 2–3). Increased levels of liver enzymes in the blood have also been observed in patients receiving moxetumomab pasudotox but without evidence of impaired hepatic function ( Kreitman et al., 2018; Kreitman et al., 2018). A diagnosis of HUS should be considered if patients have increased blood creatinine levels and decreased baseline platelet counts, and may also have, proteinuria, hematuria, decreased red blood cell counts; and/or hemoglobinuria. Patients should be advised to contact their healthcare provider if they experience any symptoms or side effects during treatment. They should also be educated on the signs of serious side effects and advised to contact emergency services if they experience symptoms of HUS and CLS.

Table 2.

SYMPTOMS OF SERIOUS SIDE EVENTS WITH MOXETUMOMAB PASUDOTOX

Side effect Symptoms
HUS  • Decrease in the amount of urine or dark urine (tea-colored)
 • Unusual bleeding or bruising of the skin
 • Stomach pain
 • Vomiting
 • Fever
 • Tiredness
 • Changes in mood or behavior
 • Confusion
 • Seizures
 • Shortness of breath
 • Fast heartbeat
CLS  • Nausea
 • Vomiting
 • Headache
 • Swelling of the face, arms, or legs
 • Fast and unexplained weight gain (gain of > 4.5 kg [10 lbs] within a week)
 • Weakness or dizziness
 • Shortness of breath
 • Decrease in the amount of urine
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CLS, capillary leak syndrome; HUS, hemolytic uremic syndrome

Counseling points for healthcare professionals

Patients with HCL are commonly well versed in their disease, especially when they have received multiple prior therapies. Patients commonly ask questions about the effectiveness of therapy and when they might know whether the drug is working. Initially, many patients are surprised at the amount of fluid that they are required to drink on a daily basis. One useful analogy is that of a bucket representing the intravascular space, which is slowly leaking. The goal is to keep the ‘bucket’ full but not overflowing, and an effective way to achieve this is to constantly add water at the same rate as the water is lost. To keep the water level constant, it is more effective to add water slowly, rather than to try to play ‘catch-up’ with large volumes after allowing the bucket to lose volume. The same analogy helps to explain why intravenous fluid is not advisable when patients ask if they can just receive the fluids this way instead. Because patients are drinking so much fluid, another common concern that can arise is ‘when will the edema go away?’ E The answer to this question is that edema will commonly decrease after 8–10 days with a resolution by day 13–15.

In addition to educating patients on the points described above a handout with the ‘dos and don’ts can be provided (Table 4).

Table 4.

MOXETUMOMAB PASUDOTOX ‘DOS AND DON’TS’ CHECKLIST FOR PATIENTS

Do Don’t
Continue to drink plenty of fluids (3–6 L every 24 hours) Take NSAIDs (with the exception of aspirin)
Elevate your legs when sitting down Engage in strenuous activity
Light exercise Drink more caffeinated beverages than non-caffeinated beverages
Contact your provider if you have any problems Take any new medication without contacting your provider first
Contact your provider prior to taking any medications not on your discharge instructions
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NSAID, non-steroidal anti-inflammatory drug

Case studies pertaining to the use of moxetumomab pasudotox in the clinic

Case 1

Case 1 was a 50-year-old male diagnosed with HCL at age 44, who had experienced a 2.5-year response to his first course of cladribine and no response to a second course of the same treatment. He initiated treatment with moxetumomab pasudotox with a baseline white blood cell count of 1.61 × 109 cells/L, an absolute neutrophil count (ANC) of 1.09 × 109 cells/L, hemoglobin levels of 15.0 g/dL, a platelet count of 86/mm3, an HCL cell count of 10.9 cells/mm3, and a spleen size of 12.5 cm. At the onset of treatment, the patient did not have any subjective symptoms other than slight fatigue. His platelet count of 86/mm3 and R/R disease qualified him to start. Platelet and HCL cell counts resolved to 125/mm3 and 0.07 cells/mm3, respectively, by cycle 1, day 29; and by cycle 2, day 4, ANC had resolved to 1.97 x 109 cells/L, consistent with a partial response to treatment. The patient reported some edema during cycle 2, which resolved by day 15. By cycle 3, day 28, disease assessment using immunohistochemistry and flow cytometry of bone marrow samples showed complete response without MRD. The patient subsequently received two further cycles of treatment with moxetumomab pasudotox, without recurrent edema, and has remained in MRD-negative CR since the last restaging at 2.5 years.

Case 2

Case 2 was a 44-year-old male who was diagnosed with HCL at age 41. Prior to treatment with moxetumomab pasudotox, the patient had received two courses of cladribine, each followed by eight weekly doses of rituximab, with barely 2 years of response to the first treatment course and no response to the second course. The patient initiated treatment with moxetumomab pasudotox with a baseline white blood cell count of 1.03 × 109 cells/L, an ANC of 0.76 × 109 cells/L, hemoglobin levels of 9.9 g/dL, a platelet count of 110/mm3, an HCL cell count of 1.5 cells/mm3, a spleen size of 14.2 cm, and creatinine levels of 0.8–1.4 mg/dL. During the first two cycles of treatment with moxetumomab pasudotox, the patient experienced mild nausea and low-grade fever that interfered with his ability to drink water. He was poorly responsive to anti-nausea agents and antibiotics but rapidly responsive to methylprednisolone. The patient continued to work full time, outside in hot weather, between treatment cycles. During cycle 2, he achieved a partial response to treatment with resolution of blood counts (white blood cell count, 2.6 × 109 cells/L; ANC, 1.79 × 109 cells/L; hemoglobin, 12.1 g/dL; platelet count, 216/mm3; HCL cell count, 0.04 cells/mm3). Prior to cycle 3, peak creatinine level was 1.32 mg/dL. During cycle 3, the patient’s platelet count decreased from 168 mm3 to 42 mm3, and his creatinine levels increased from 1.12 mg/dL to 1.63 mg/dL between days 1 and 8, causing suspicion of HUS. Schistocytes were checked and only 1.5 schistocytes per high power field were noted. The patient noted symptoms of decreased appetite and dark urine on the morning of day 7, which resolved after receiving oral methylprednisolone at a dose of 60 mg. He was diagnosed with a HUS-like reaction, rather than actual HUS, owing to the lack of significant schistocytosis. The patient travelled home by plane on day 9 with improvements in platelet count and creatinine levels (65/mm3 and 1.61 mg/dL, respectively). By days 12–13, platelet count was 172/mm3, and creatinine levels were 1.51 mg/dL; by day 15, platelet count and creatinine levels were 227/mm3 and 1.29 mg/dL, respectively. The patient achieved CR by cycle 3,day 28; he was not retreated, owing to the HUS-like reaction, but remains in CR with the last restaging 2.5 years after treatment

Case 3

Case 3 was a 52-year-old male who was diagnosed with HCL at age 42. The patient had received two prior courses of single-agent cladribine, one course of rituximab, and one course of cladribine combined with rituximab; he had responded to each but relapsed three years after the last treatment. The patient began treatment with moxetumomab pasudotox with the following clinical parameters: white blood cell count, 1.39 × 109 cells/L; ANC, 0.59 × 109 cells/L; hemoglobin level, 13.4 g/dL; platelet count, 68 mm3; HCL cell count, 2.1 cells/mm3; and a spleen size of 163 mm (non-palpable). He responded to treatment with moxetumomab pasudotox after one treatment cycle, and by day 28, his white blood cell count was 2.83 × 109 cells/L. In addition, ANC was 1.61 × 109 cells/L, hemoglobin levels were 13.4 g/dL, platelet count was 129 mm3, and hairy cells were undetectable in peripheral blood. The patient began to experience nausea on cycle 2, day 5, which resolved quickly after oral administration of dexamethasone 4 mg. On day 7, the nausea recurred and then resolved after oral administration of dexamethasone 12 mg. The patient experienced further nausea during cycles 4–6, which was relieved by oral administration of 4 mg of dexamethasone. No side effects of HUS or CLS occurred during treatment. Disease restaging, first performed on day 35 of cycle 6, showed findings consistent with MRD-negative CR. At this time point, the patient had white blood cell counts of 5.18 × 109 cells/L, ANC counts of 3.6 × 109 cells/L, hemoglobin levels of 14.7 g/dL, a platelet count of 191 mm3, and a spleen size of 137 mm. He has remained in MRD-negative CR with last restaging of disease 2.5 years post-treatment.

Summary and conclusions

Moxetumomab pasudotox shows great promise in improving treatment outcomes in patients with R/R HCL, and nurses will play a pivotal role in the administration and monitoring of patients receiving this new treatment. It is essential for the care and treatment of these patients that nurses become educated about this newly FDA-approved drug therapy, specifically regarding:

  • Indications: multiply relapsed HCL

  • Contraindications: renal insufficiency

  • Infusion: dosing, and cycles

  • Side effect management and prevention: HUS, CLS, edema and nausea.

Guidance from nurses and other healthcare professionals involved in the administration of moxetumomab pasudotox to patients (Figure 3) will help reduce possible side effects, optimize moxetumomab pasudotox treatment and thus patient outcomes.

Figure 3.

Figure 3.

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HEALTHCARE PROVIDER FLOWCHART FOR THE USE OF MOXETUMOMAB PASUDOTOX

H2, Histamine H2 receptor; IV, intravenously

IMPLICATIONS FOR PRACTICE.

  1. Nurses play a pivotal role in the management of patients receiving moxetumomab pasudotox.

  2. Monitoring of clinical parameters before, during and after administration of moxetumomab pasudotox is important for optimal treatment.

  3. Patients receiving moxetumomab pasudotox should be educated on how to achieve the best outcomes from treatment.

Acknowledgments

Medical writing support was provided by Lucy Ambrose DPhil of Oxford PharmaGenesis, Oxford, UK, and was funded by AstraZeneca.

Funding:

This review was funded by AstraZeneca

Footnotes

Financial disclosures:

Robert J. Kreitman is the co-inventor on the NIH patent for moxetumomab pasudotox; Julie Feurtado has no disclosures to report

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