Moxetumomab Pasudotox-tdfk (Lumoxiti)

Number: 0943

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of moxetumomab pasudotox-tdfk (Lumoxiti) is required of all Aetna participating providers and members in applicable plan designs. For precertification of moxetumomab pasudotox-tdfk call (866) 752-7021, (866) 503-0857 (Medicare), or fax (866) 267-3277.

Aetna considers moxetumomab pasudotox-tdfk (Lumoxiti) medically necessary for the treatment of individuals with relapsed or refractory hairy cell leukemia (HCL) when the following criteria are met:

• Member has received prior treatment with at least 2 systemic therapies, including one purine nucleoside analog; and
• Member has not previously received 6 or more cycles of treatment with moxetumomab pasudotox-tdfk.

Aetna considers continued treatment in members requesting reauthorization medically necessary when the member has not previously received 6 or more cycles of treatment with  moxetumomab pasudotox-tdfk, and member has not experienced disease progression or an unacceptable toxicity while on current regimen.

Aetna considers moxetumomab pasudotox-tdfk treatment experimental and investigational for all other indications because its effectiveness for other indications has not been established. 

Dosing Recommendations

The recommended dosage of Lumoxiti is 0.04 mg/kg as an intravenous infusion over 30 minutes on Days 1, 3, and 5 of each 28-day cycle. Pre-medicate with an acetaminophen antipyretic, antihistamine, and H2receptor antagonist prior to all infusions. Continue treatment for a maximum of 6 cycles, disease progression, or unacceptable toxicity.

Lumoxiti is available as a 1 mg single-dose vial for reconstitution and further dilution.

Source: AstraZeneca, 2020.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Lumoxiti is a CD22-directed cytotoxin indicated for the treatment of 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).

Hairy Cell Leukemia

Hairy cell leukemia (HCL) is a rare type of chronic B cell leukemia characterized by the accumulation of small mature B cell lymphoid cells with abundant cytoplasm and "hairy" projections within the peripheral blood, bone marrow, and splenic red pulp. These leukemic cells typically invade the bone marrow and spleen and result in a variety of systemic symptoms including fatigue, weakness, splenomegaly and/or hepatomegaly, pancytopenia, and increased risk of infection. Not all patients diagnosed with HCL require immediate treatment. Asymptomatic disease is best managed by close observation until symptoms develop. According to the NCCN Hairy Cell Leukemia guidelines (v.2.2019), indications for treatment initiation could include symptoms such as excessive fatigue, splenomegaly/hepatomegaly causing physical discomfort, a weight loss greater than 10% within the past six months, cytopenias, progressive lymphocytosis or lymphadenopathy.

Once the decision is made to initiate therapy, purine analogs (i.e., cladribine or pentostatin) are the preferred initial treatment for most patients with symptomatic HCL. Durable responses are seen in greater than 90 percent of patients with a median progression-free survival of 9 to 11 years. Cladribine and Pentostatin are also effective for the treatment of relapsed HCL. Second line therapy for patients with relapsed/refractory HCL depends on the duration of remission. If HCL relapse occurs 2 years or more after achieving complete response to the initial purine therapy, they could be retreated with the same purine analog with or without rituximab, or with an alternate purine analog (with or without rituximab) or with rituximab monotherapy. Alternatively, if the relapse occurred within 2 years of achieving complete response to initial therapy, participation in a clinical trial, a trial of another purine analog (with or without rituximab), rituximab monotherapy, vemurafenib, or interferon alpha may be treatment options in these cases. For disease that continues to progress after second-line therapy, options in the past have included clinical trial, ibrutinib, or vemurafenib (with or without rituximab).

On September 13, 2018, the FDA approved moxetumomab pasudotox-tdfk (Lumoxiti) injection for intravenous use for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL. The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients with histologically confirmed HCL (n=77)or HCL variant (n=3) with a need for therapy based on presence of cytopenias or splenomegaly and who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog (Kreitman et al 2018). Eligible patients had serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 60 mL/min as estimated by the Cockcroft Gault equation. The median age was 60 years (range: 34 to 84) years, 79% were male, and 94% were Caucasian. At baseline, 98% of patients had an ECOG performance status of 0 or 1. The median number of prior treatments was 3 (range: 2 to 11); all patients received prior purine nucleoside analog therapy, including 29% in combination with rituximab. The most common other prior treatment regimens were rituximab monotherapy (51%), interferon-alpha (25%), and a BRAF inhibitor (18%). At baseline, 33% (26/80) of patients had low hemoglobin (< 10 g/dL), 68% (54/80) of patients had neutropenia (< 1000/mm3), and 84% (67/80) patients had baseline platelet counts < 100,000/mm3. About 35% of patients had enlarged spleens (≥ 14 cm, assessed by BICR) at baseline. Patients received Lumoxiti 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. The median duration of follow-up was 16.7 months (range: 2 to 49). An independent review committee (IRC) performed efficacy evaluations using blood, bone marrow, and imaging criteria adapted from previous HCL studies and consensus guidelines.

The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Hematologic remission was defined as hemoglobin ≥ 11 g/dL, neutrophils ≥ 1500/mm3, and platelets ≥ 100,000/mm3 without transfusions or growth factor for at least 4 weeks. Thirty percent of patients (24/80 patients) in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent. The median time to objective response rate (ORR) and CR was 5.7 months (range: 1.8 to 12.9) and 5.9 months (range 1.8 to 13.2), respectively. Sixty-four patients (80%) had normalization of hematologic parameters and achieved hematologic remission, with a median time to hematologic remission of 1.1 months (range: 0.2 to 13) and with a median duration of hematologic remission not reached (range: 0.3 to 48.2+). Complete response, as defined by pathology, imaging, hepatomegaly and lymphadenopathy, and normalization of hematologic parameters, was 41% (33/80 patients), and among the complete responders, 27 (85%) achieved minimal residual disease negativity as assessed by immunohistochemistry.

Kreitman et al (2012) conducted a phase I dose-escalation trial assessing safety and response of recombinant immunotoxin moxetumomab pasudotox (CAT-8015, HA22) in chemotherapy-resistant hairy cell leukemia (HCL). Eligible patients had relapsed/refractory HCL after ≥ two prior therapies and required treatment because of abnormal blood counts. Patients received moxetumomab pasudotox 5 to 50 μg/kg every other day for three doses (QOD ×3), with up to 16 cycles repeating at ≥ 4-week intervals if patients did not experience disease progression or develop neutralizing antibodies. Twenty-eight patients were enrolled, including three patients each at 5, 10, 20, and 30 μg/kg, four patients at 40 μg/kg, and 12 patients at 50 μg/kg QOD ×3 for one to 16 cycles each (median, four cycles). Dose-limiting toxicity was not observed. Two patients had transient laboratory abnormalities consistent with grade 2 hemolytic uremic syndrome with peak creatinine of 1.53 to 1.66 mg/dL and platelet nadir of 106,000 to 120,000/μL. Drug-related toxicities in 25% to 64% of the 28 patients included (in decreasing frequency) grade 1 to 2 hypoalbuminemia, aminotransferase elevations, edema, headache, hypotension, nausea, and fatigue. Of 26 patients evaluable for immunogenicity, 10 patients (38%) made antibodies neutralizing more than 75% of the cytotoxicity of 1,000 ng/mL of immunotoxin, but this immunogenicity was rare (5%) after cycle 1. The overall response rate was 86%, with responses observed at all dose levels, and 13 patients (46%) achieved complete remission (CR). Only 1 CR lasted less than 1 year, with the median disease-free survival time not yet reached at 26 months. The authors concluded that moxetumomab pasudotox at doses up to 50 μg/kg QOD ×3 has activity in relapsed/refractory HCL and has a safety profile that supports further clinical development for treatment of this disease.

The prescribing information for Lumoxiti includes a Boxed Warning to advise health care professionals and patients about the risk of developing capillary leak syndrome, a condition in which fluid and proteins leak out of tiny blood vessels into surrounding tissues. Symptoms of capillary leak syndrome include difficulty breathing, weight gain, hypotension, or swelling of arms, legs and/or face. The Boxed Warning also notes the risk of hemolytic uremic syndrome, a condition caused by the abnormal destruction of red blood cells. Patients should be made aware of the importance of maintaining adequate fluid intake, and blood chemistry values should be monitored frequently. Other serious warnings include: decreased renal function, infusion-related reactions and electrolyte abnormalities. Lumoxiti is not recommended for patients with severe renal impairment, and women who are breastfeeding should not be given Lumoxiti. Common side effects of Lumoxiti include infusion-related reactions, swelling caused by excess fluid in body tissue (edema), nausea, fatigue, headache, fever (pyrexia), constipation, anemia and diarrhea.

Acute Lymphoblastic Leukemia

Shah and colleagues (2020) stated that in a multi-center, phase-I clinical trial of children with relapsed/refractory acute lymphoblastic leukemia (ALL), moxetumomab pasudotox showed a manageable safety profile and preliminary evidence of clinical activity.  In an international, multi-center, phase-II clinical trial, these researchers further examined efficacy.  This study enrolled children with relapsed/refractory B-cell precursor ALL who received moxetumomab 40 µg/kg intravenously every other day, for 6 doses per 21-day cycle.  The primary objective was to evaluate the CR rate; secondary objectives included safety, pharmacokinetics, and immunogenicity evaluations.  A total of 32 patients (median age of 10 years) were enrolled at 16 sites; 30 received study drug and were evaluable for safety; 28 were evaluable for response.  The ORR was 28.6 %, with 3 patients (10.7 %) achieving morphologic CR, and 5 patients (17.9 %) achieving partial response (PR).  Disease progression occurred in 11 patients (39.3 %); 10 patients (33.3 %) experienced at least 1 treatment-related serious adverse event (SAE), including capillary leak syndrome (CLS; n = 6), hemolytic uremic syndrome (HUS; n = 4), and treatment-related death (n = 1) from pulmonary edema.  No differences were observed in inflammatory markers in patients who did or did not develop CLS or HUS.  The authors concluded that despite a signal for clinical activity, this phase-II clinical trial was terminated at interim analysis for a CR rate that did not reach the stage 1 target.  Moreover, these researchers stated that pre-clinical data suggested enhanced efficacy of moxetumomab via continuous infusion or in combination regimens; therefore, further studies designed to optimize the safety and efficacy of moxetumomab in pediatric ALL may be warranted.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96413	Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
HCPCS codes covered if selection criteria are met:
J9313	Injection, moxetumomab pasudotox-tdfk, 0.01 mg
Other HCPCS codes related to the CPB:
J7500	Azathioprine, oral, 50 mg
J7501	Azathioprine, parenteral, 100 mg
J9065	Injection, cladribine, per 1 mg
J9185	Injection, fludarabine phosphate, 50 mg
J9268	Injection, pentostatin, 10 mg
S0108	Mercaptopurine, oral, 50 mg
ICD-10 codes covered if selection criteria are met:
C91.40	Hairy cell leukemia not having achieved remission [refractory HCL]
C91.42	Hairy cell leukemia, in relapse
ICD-10 codes not covered for indications listed in the CPB:
C91.41	Hairy cell leukemia, in remission

The above policy is based on the following references: