September 13, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761104s000lbl.pdf

On Sept. 13, 2018, the Food and Drug Administration approved moxetumomab pasudotox-tdfk (LUMOXITI, AstraZeneca Pharmaceuticals LP), a CD22-directed cytotoxin indicated for adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least two prior systemic therapies, including treatment with a purine nucleoside analog (PNA).

Approval was based on Study 1053 (NCT01829711) in patients with histologically confirmed HCL or HCL variant requiring treatment based on presence of cytopenias or splenomegaly and who had received prior treatment with at least two systemic therapies, including one PNA. Eligible patients had serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 60 mL/min as estimated by the Cockcroft Gault equation. A total of 80 patients were enrolled; 77 with classic HCL and 3 with HCL variant. Patients received moxetumomab pasudotox-tdfk, 0.04 mg/kg as an intravenous infusion, over 30 minutes on days 1, 3, and 5 of each 28-day cycle for a maximum of 6 cycles or until documentation of complete response (CR), disease progression, or unacceptable toxicity.

Efficacy in HCL was evaluated by the blinded independent review committee (IRC)-assessed rate of durable CR confirmed by maintenance of hematologic remission (hemoglobin ≥ 11 g/dL, neutrophils ≥ 1500/mm3, and platelets ≥ 100,000/mm3 without transfusions or growth factor for at least 4 weeks) more than 180 days after IRC-assessed CR. The IRC-assessed durable CR rate was 30% (24/80 patients; 95% CI: 20, 41). The IRC-assessed CR rate was 41% (33/80 patients; 95% CI 30,53).

The most common non-laboratory adverse reactions (≥20%) of any grade were infusion related reactions, edema, nausea, fatigue, headache, pyrexia, constipation, anemia, and diarrhea. The most common grade 3 or 4 adverse reactions (reported in at least ≥ 5% of patients) were hypertension, febrile neutropenia, and hemolytic uremic syndrome (HUS). Adverse reactions resulting in permanent discontinuation of moxetumomab pasudotox-tdfk occurred in 15% (12/80) of patients. The most common adverse reaction leading to discontinuation was HUS (5%). The most common adverse reactions resulting in dose delays, omissions, or interruptions was pyrexia (3.8%).

The recommended dose of moxetumomab pasudotox-tdfk is 0.04 mg/kg administered as a 30-minute intravenous infusion on days 1, 3, and 5 of each 28-day cycle for a maximum of 6 cycles or until occurrence of disease progression or unacceptable toxicity.

View full prescribing Information for Lumoxiti.

FDA granted this application fast track and priority review designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics. Moxetumomab pasudotox-tdfk has also been granted Orphan Drug Designation for the treatment of HCL.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Moxetumomab Pasudotox-tdfk for Relapsed or Refractory Hairy Cell Leukemia

Authors: Matthew Newman, PharmD BCOP
Clinical Pharmacist Practitioner, Hematologic Malignancies
The Johns Hopkins Hospital
Baltimore, MD

Carmen Nobre, PharmD BCOP
Clinical Pharmacy Specialist, Leukemia and Lymphoma
The Johns Hopkins Hospital
Baltimore, MD

What is the potential role for moxetumomab pasudotox-tdfk in the treatment of relapsed or refractory (R/R) hairy cell leukemia (HCL)?

  • Moxetumomab pasudotox-tdfk is a novel recombinant immunotoxin targeting CD22. It consists of a murine immunoglobulin variable domain genetically fused to a truncated form of Pseudomonas exotoxin, PE38.1,2
  • In an open-label phase 3 single-arm trial (Study 1053, NCT01829711), 80 patients with R/R HCL with at least two prior therapies, including at least one purine analog, received intravenous (IV) moxetumomab pasudotox-tdfk 0.04 mg/kg over 30 minutes on days 1, 3, and 5.3 Durable complete response (CR) was achieved in 30%, CR in 41%, and objective response in 75%, with 80% achieving hematologic remission. Adverse effects included peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Less common, yet serious, adverse effects included haemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%). Neutropenia and decreased neutrophil count occurred infrequently (in 5% and 7.5% of patients, respectively).
  • A long-term follow-up study of 21 patients with R/R HCL treated with moxetumomab pasudotox-tdfk 0.05 mg/kg IV on days 1, 3, and 5 in 4-week cycles, plus 12 patients from a previously reported study, found CR in 64% (median CR duration 42.4 months) and overall response in 88% of patients.4 Bone marrow aspirate flow cytometry was performed for minimal residual disease (MRD) assessment. The median CR duration was longer in MRD-negative patients (n = 11) compared with MRD-positive patients (n = 9) (42.1 months vs. 13.5 months, p < .001). Most patients achieving MRD negativity remained in CR (10 patients), of which 9 patients were without MRD at the time of the study conclusion. Although the significance of MRD in HCL is not yet clearly defined, outcomes appear to be improved in patients achieving MRD negativity.5,6
  • Moxetumomab pasudotox-tdfk was approved by the U.S. Food and Drug Administration in September 2018 for the treatment of adult patients with R/R HCL who had received at least two prior systemic therapies, including treatment with a purine analog.
  • Patients with R/R HCL who are no longer responding to, or who may not tolerate further treatment with, purine analogs or alternative therapies may be good candidates for treatment with moxetumomab pasudotox-tdfk. This agent has been added to the National Comprehensive Cancer Network (NCCN) guidelines as a Category-2A recommendation in this setting.7

What role can the pharmacist play in the management of patients on moxetumomab pasudotox-tdfk?2

  • Pharmacists should be aware that moxetumomab pasudotox-tdfk carries a black-box warning for capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS) and warnings and precautions for infusion-related reactions, renal dysfunction, and electrolyte abnormalities.
    • CLS occurred in 34% of patients in clinical trials and requires immediate medical attention (typically hospitalization); management may include judicious use of hydration and diuretics, with adjunctive corticosteroids. Assess weight and vital signs prior to each infusion. If CLS is suspected, assess oxygen saturation and evaluate for pulmonary edema and serosal effusions.
    • HUS occurred in 7% of patients in clinical trials and was resolved in all cases by permanent discontinuation of moxetumomab pasudotox-tdfk. Assess hemoglobin, platelet count, and serum creatinine prior to each infusion and on day 8. If HUS is suspected, check lactate dehydrogenase, indirect bilirubin, and blood-smear schistocytes for evidence of hemolysis. Management may include aggressive supportive care, fluids, and hemodynamic monitoring.
  • To prevent serious adverse events, patients should receive adequate hydration. This includes 1 L of isotonic IV hydration over 2–4 hours (0.5 L in patients under 50 kg) prior to, and following, each infusion. Additionally, patients should be advised to drink up to 3 L of oral hydration per day on days 1 through 8 of each cycle (up to 2 L per day in patients under 50 kg).
  • Pharmacists should ensure that premedications including an antihistamine, acetaminophen, and a histamine-2 receptor antagonist are administered 30–90 minutes prior to the infusion.
  • Following an infusion, an antihistamine and an antipyretic may be continued for up to 24 hours. An oral corticosteroid may be given postinfusion to decrease nausea and vomiting.
  • If a severe infusion-related reaction occurs, a steroid premedication should be administered prior to each subsequent infusion.
  • Low-dose aspirin may be considered on days 1 through 8 of each cycle for thromboprophylaxis; it was administered in Study 1053 to patients with a platelet count above 100,000/mm3.

Clinical Pearls

  • Moxetumomab pasudotox-tdfk is available in a single-dose vial containing 1 mg of preservative-free lyophilized drug powder that is reconstituted with 1.1 mL sterile water for injection. An IV solution stabilizer is provided in a separate package and is a single-dose vial containing 1 mL of sterile, preservative-free solution.
  • The IV infusion is prepared by adding 1 mL of the IV solution stabilizer to a 50-mL infusion bag of 0.9% sodium chloride, prior to adding the drug. It is important to note that only 1 mL of IV solution stabilizer is needed to prepare a single dose of moxetumomab pasudotox-tdfk, regardless of the dose. Do not use the IV solution stabilizer to reconstitute the drug vial.
  • Both moxetumomab pasudotox-tdfk and IV solution stabilizer should be refrigerated and protected from light. Do not freeze or shake.
  • Treatment may continue for a maximum of six 28-day cycles, until the disease progresses or an unacceptable level of toxicity is reached, whichever occurs first.
  • Moxetumomab pasudotox-tdfk was not evaluated in patients with creatinine clearance of 29 mL/min or less, and its use is not recommended in this population.
  • The Lumoxiti Patient Savings Program is available to patients who are residents of the United States or Puerto Rico and have commercial insurance. Most eligible patients may pay $0 per infusion and may have up to $26,000 of annual assistance toward out-of-pocket costs of the medication and up to $100 of infusion costs per administration.8

References

  1. Kreitman RJ, Pastan I. Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox. Clin Cancer Res. 2011;17:6398-6405.
  2. Lumoxiti [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP, 2018.
  3. Kreitman RJ, Dearden C, Zinzani PL, et al. Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia. Leukemia. 2018;32:1768-1777.
  4. Kreitman RJ, Tallman MS, Robak T, et al. Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up. Blood. 2018;131:2331-2334.
  5. Tallman MS, Hakimian D, Kopecky KJ, et al. Minimal residual disease in patients with hairy cell leukemia in complete remission treated with 2-chlorodeoxyadenosine or 2-deoxycoformycin and prediction of early relapse. Clin Cancer Res. 1999;5:1665-1670.
  6. Wheaton S, Tallman MS, Hakimian D, Peterson L. Minimal residual disease may predict bone marrow relapse in patients with hairy cell leukemia treated with 2-chlorodeoxyadenosine. Blood. 1996;87:1556-1560.
  7. National Comprehensive Cancer Network. Hairy Cell Leukemia. Version 3.2019. Available at https://www.nccn.org/professionals/physician_gls/pdf/hairy_cell.pdf. Accessed November 25, 2018.
  8. AstraZeneca Pharmaceuticals. Helping patients access the care they need. Available at https://www.astrazenecaspecialtysavings.com/pdf/LUMOXITI_Affordability_Brochure.pdf. Accessed November 5, 2018