Blinatumomab (Blincyto)

Number: 0891

Policy

Aetna considers blinatumomab (Blincyto) medically necessary for treatment of B-cell precursor acute lymphoblastic leukemia (ALL) when all of the following criteria are met:

• As single-agent therapy; and
• Corticosteroids will be given as premedication prior to Blincyto infusion; and
• The B-cells must be CD19-positive as confirmed by testing or analysis; and
• The member meets one of the following:
   

  • The member has Philadelphia chromosome positive disease and meets one of the following:

    • Member has relapsed or refractory disease and had an inadequate response or intolerance to a tyrosine kinase inhibitor (TKI) (e.g., imatinib, dasatinib); or
    • Member has less than complete response following induction therapy; or 
    • Member has minimal residual disease positive (MRD+) at the end of consolidation therapy, or
      
      

  • The member has Philadelphia chromosome negative disease and meets one of the following:

    • Member has relapsed or refractory disease; or
    • Blincyto will be used as consolidation therapy with minimal residual disease positive (MRD+) following a complete response to induction therapy; or
    • Blincyto will be used for minimal residual disease positive (MRD+) after consolidation therapy; or
      
      
  • The member has Philadelphia chromosome like disease that is minimal residual disease positive (MRD+) after consolidation therapy.

Aetna considers continued treatment with blinatumomab medically necessary for members requesting authorization for continuation of therapy when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Aetna considers blinatumomab experimental and investigational for all other indications including the following (not an all-inclusive list):

• Acute myeloid leukemia
• Melanoma
• Non-Hodgkin's lymphoma (e.g., Burkitt lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma).

Aetna considers combined blinatumomab and tyrosine kinase inhibitor for the treatment of relapsed Philadelphia chromosome-positive leukemia experimental and investigational because the effectiveness of this approach has not been established.

Aetna considers combined blinatumomab and donor lymphocyte infusion for the treatment of mixed-phenotype acute leukemia experimental and investigational because the effectiveness of this approach has not been established.

Dosing Recommendations

Blinatumomab is available as Blincyto in 35 mcg, single-use vials for reconstitution.  Blinatumomab is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm. The labeling states that it is important to strictly follow instructions for preparation (including admixing) and administration to prevent overdose and underdose. Premedicate with prednisone or equivalent dexamethasone. See Full Prescribing Information for recommended dose by patient weight and schedule. Patients greater than or equal to 45 kg receive a fixed-dose. For patients less than 45 kg, the dose is calculated using the patient’s body surface area (BSA).

For the treatment of Relapsed or Refractory B-cell Precursor ALL, the labeling for Blincyto recommends hospitalization for the first 9 days of the first cycle and the first 2 days of the second cycle. A treatment course consists of up to 2 cycles of Blincyto for induction followed by 3 additional cycles for consolidation and up to 4 additional cycles of continued therapy. A single cycle of treatment of Blincyto induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days). A single cycle of treatment of Blincyto continued therapy consists of 28 days of continuous intravenous infusion followed by a 56-day treatment-free interval (total 84 days). 

For the treatment of MRD-positive B-cell Precursor ALL, the labeling for Blincyto recommends hospitalization for the first 3 days of the first cycle and the first 2 days of the second cycle. A treatment course consists of 1 cycle of Blincyto for induction followed by up to 3 additional cycles for consolidation. A single cycle of treatment of Blincyto induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).

Source: Amgen, 2020.

Background

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

• Blincyto is indicated for the treatment of B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and children.
• Blincyto is indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children.

Compendial Uses

• Philadelphia chromosome negative or Philadelphia chromosome like B-cell precursor acute lymphoblastic leukemia (ALL) that is minimal residual disease positive (MRD+) after consolidation therapy.
• Philadelphia chromosome positive (Ph-positive) B-cell precursor acute lymphoblastic leukemia (ALL) with less than complete response or MRD+ at end of consolidation.

Blincyto (blinatumomab) is a bispecific CD19-directed CD3 T-cell engager. Blincyto (blinatumomab) binds to CD19 expressed on the surface of cells of B‐lineage origin and CD3 expressed on the surface of T cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B cells. Blincyto (blinatumomab) mediates the formation of a synapse between the T cell and the tumor cell, upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, which result in redirected lysis of CD19+ cells.

B-cell Precursor Acute Lymphoblastic Leukemia (ALL)

The U.S. Food and Drug Administration (FDA) approved blinatumomab (Blincyto) (Amgen, Thousand Oaks, CA) to treat patients with relapsed or refractory Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia (B-cell ALL) (FDA, 2014). This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

The FDA granted Blincyto breakthrough therapy designation, priority review and orphan product designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies; the drug had the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition; and the drug is intended to treat a rare disease, respectively (FDA, 2014).  

The FDA approval of Blincyto was based on results of Amgen's '211 trial, a phase 2, multicenter, single-arm open-label study involving 185 adults with Philadelphia chromosome-negative relapsed or refractory precursor B-cell ALL (Amgen, 2014).  Eligible patients were greater than 18 years of age with Ph- relapsed or refractory B-cell precursor ALL.  Relapsed or refractory was defined as relapsed with first remission duration of less than 12 months in the first salvage, or relapsed or refractory after first salvage therapy, or relapsed within 12 months of allogeneic hematopoietic stem cell transplantation (HSCT), and had greater than 10 % blasts in bone marrow.  All participants were treated with blinatumomab for at least 4 weeks via infusion.  Of the 185 patients evaluated in the trial, 41.6 % (77/185; 95 % confidence interval [CI]: 34.4 to 49.1) achieved complete remission or complete remission with partial hematologic recovery (CR/CRh*) within 2 cycles of treatment with blinatumomab, which was the primary end-point of the study.  The majority of responses (81 % [62/77]) occurred within the first cycle of treatment.  Among patients who achieved CR/CRh*, 39 % (30/77) went on to HSCT, and 75.3 % (58/77 95 %CI: 64.2 to 84.4) achieved minimal residual disease (MRD) response. 

Studies used to assess effectiveness of Blincyto (blinatumomab) defined relapsed or refractory as: relapsed with first remission duration of ≤ 12 months in first salvage or relapsed or refractory after first salvage therapy or relapsed within 12 months of allogeneic hematopoietic stem cell transplantation [HSCT], and had ≥ 10% blasts in bone marrow.

Blincyto was approved under the FDA’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients (FDA, 2014).  The FDA is requiring the manufacturer to conduct a study to verify that the drug improves survival in participants with relapsed or refractory Philadelphia-negative precursor B-cell ALL. 

Blincyto carries a boxed warning that some clinical trial participants had problems with cytokine release syndrome (CRS), or neurological toxicities which may be life threatening or fatal (FDA, 2014).  The labeling recommends that blinatumomab be interrupted or discontinued in patients experiencing these side effects.

The most common adverse reactions (greater than or equal to 20 %) were pyrexia (62 %), headache (36 %), peripheral edema (25 %), febrile neutropenia (25 %), nausea (25 %), hypokalaemia (23 %), rash (21 %), tremor (20 %) and constipation (20 %) (Amgen, 2014).  Serious adverse reactions were reported in 65 % of patients.  The most common serious adverse reactions (greaterthan or equal to 2 %) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia and headache.

Life-threatening or fatal CRS occurred in patients receiving blinatumomab (Amgen, 2014).  The labeling states that manifestations of CRS may be indistinguishable from Infusion reactions.  The labeling states that patients should be closely monitored for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).  The labeling recommends that blinatumomab be interrupted or discontinued if CRS occurs. 

Approximately 50 % of patients receiving blinatumomab in clinical trials experienced neurological toxicities (Amgen, 2014).  Severe, life-threatening, or fatal neurological toxicities occurred in approximately 15 % of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders.  The median time to onset of any neurological toxicity was 7 days.  The labeling recommends monitoring patients for signs or symptoms and recommends interrupting or discontinuing blinatumomab if these occur. 

Approximately 25 % of patients receiving blinatumomab experienced serious infections, some of which were life-threatening or fatal (Amgen, 2014).  The labeling recommends administration of prophylactic antibiotics surveillance testing as appropriate during treatment.  The labeling states that patients should be monitored for signs or symptoms of infection and treated appropriately, including interruption or discontinuation of blinatumomab as needed.

Life-threatening or fatal tumor lysis syndrome (TLS) has been observed with blinatumomab (Amgen, 2014).  The labeling recommends use of preventive measures, including pre-treatment non-toxic cytoreduction and on treatment hydration, during blinatumomab treatment.  Patients should be monitored for signs and symptoms of TLS and blinatumomab interrupted or discontinued as needed to manage these events.

Neutropenia and febrile neutropenia, including life-threatening cases, have been observed with blinatumomab  (Amgen, 2014).  Appropriate laboratory parameters should be monitored during blinatumomab infusion and blinatumomab should be interrupted if prolonged neutropenia occurs.

Due to the possibility of neurological events, including seizures, patients receiving blinatumomab are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while blinatumomab is being administered (Amgen, 2014).

Transient elevations in liver enzymes have been associated with blinatumomab treatment (Amgen, 2014).  The majority of these events were observed in the setting of CRS.  The median time to onset was 15 days.  Grade 3 or greater elevations in liver enzymes occurred in 6 % of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1 % of patients. ALT, AST, gamma-glutamyl transferase (GGT), and TBILI should be monitored prior to the start of and during blinatumomab treatment.  The labeling states that blinatumomab treatment should be interrupted if transaminases rise to greater than 5 times the upper limit of normal (ULN) or if TBILI rises to greater than 3 times ULN.

Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving blinatumomab, especially in patients previously treated with cranial irradiation and anti-leukemic chemotherapy (Amgen, 2014).

Blinatumomab is contraindicated to patients with known hypersensitivity to blinatumomab or to any component of the product formulation (Amgen, 2014).  The labeling of Blincyto recommends that patients be monitored for signs and symptoms of infection and treated appropriately.  The labeling states that patients should be advised to refrain from driving and engaging in hazardous occupations or activities such as driving, operating heavy or potentially dangerous machinery while blinatumomab is being administered.

The FDA approved Blincyto with a Risk Evaluation and Mitigation Strategy (REMS), which consists of a communication plan to inform health care providers about the serious risks and the potential for preparation and administration errors (FDA, 2014).

Acute Myeloid Leukemia

Sasine and Schiller (2015) noted that high-risk acute myeloid leukemia (AML) is defined by clinical and biologic features that predict for poor response to induction chemotherapy and high risk of relapse.  Despite even the most aggressive and well-developed strategies for care, most patients succumb to the disease.  No currently available treatment has demonstrated consistent efficacy in terms of remission induction or long-term survival.  These researchers highlighted some of the emerging strategies to treat high-risk AML with an emphasis on clinical trials of novel strategies currently enrolling patients.  Targeted molecular therapies, novel cytotoxics, and immune-based therapies are under investigation for the management of high-risk AML.  Some of the agents covered include TKIs targeted to AML specific oncoproteins, nanoparticle formulations of existing drugs, nucleoside analogs, monoclonal antibodies, chimeric antigen receptors, bi-specific T-cell engaging antibodies, and vaccines.  As the understanding of the biology of AML has improved, targeted therapy for AML has emerged, offering to change not only response rate, but also the nature of response.  Differentiation, rather than necrosis or apoptosis, is often seen in response to targeted agents and may be seen more frequently in the future.  Interventions that might be more widely used in the near future include FLT3 inhibitors and nanoparticle formulations of drugs already known to have activity in the disease.  Long term immune therapy holds significant promise.

Combination Therapy with Blinatumomab 

Assi and colleagues (2017) noted that the treatment of Philadelphia chromosome-positive (Ph+) ALL has been revolutionized with the introduction of TKIs and the combination of these agents with chemotherapy.  Blinatumomab is a bispecific anti-CD3/CD19 monoclonal antibody with clinical activity as single-agent in the relapsed setting and independent of BCR-ABL1 mutational status, including T315I.  The combination of blinatumomab with a TKI may further improve outcomes for this high-risk population, including higher eradication of MRD and minimize the use of chemotherapy.  These investigators retrospectively studied 12 adults with relapsed/refractory Ph+ ALL (n = 9) and chronic myeloid leukemia (CML) in blast crisis (n = 3), treated with the combination blinatumomab and a TKI (ponatinib, n = 8; dasatinib, n = 3; bosutinib, n = 1).  All patients have previously failed at least 1 line of chemotherapy, including allogeneic stem cell transplantation (ASCT), and 1 class of TKIs.  Patients were treated for either overt hematologic relapse (n = 6) or persistent MRD following other regimens (n = 6).  The complete hematologic, cytogenetic, and molecular response rates were 50 % (3/6), 71 % (5/7), and 75 % (9/12), respectively; 2 cases of grade 2 CRS were observed, all of which resolved with steroids and tocilizumab.  No cardiovascular AEs were encountered.  With a median follow-up of 8 months, the median survival was not reached; the 6-month and 1-year overall survival (OS) rates were 73 %.  The authors concluded that the combination of blinatumomab with TKI was safe and effective in patients with relapsed/refractory Ph+ disease.; prospective studies are needed.

Durer and colleagues (2019) stated that blinatumomab and donor lymphocyte infusion (DLI) combination is a promising cancer therapy, whereby blinatumomab might achieve an initial reduction in leukemic-cell burden using T cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission.  These researchers presented the case of a 51-year old woman with mixed phenotype acute leukemia who had a hematologic relapse 3 months after she received total body irradiation (TBI)-based myeloablative allogeneic hematopoietic stem cell transplantation from an unrelated human leukocyte antigen (HLA)-matched (10/10) donor and achieved complete remission (CR) with MRD negativity by multi-parameter flow cytometry using the combination of blinatumomab and DLI.  The authors concluded that to the best of their knowledge, this was the first report to describe the use of blinatumomab and DLI combination therapy in the treatment of B/myeloid mixed phenotype acute leukemia.

Choi and colleagues (2020) noted that the therapeutic approach for r/r ALL remains to be a challenge.  In this single-case study, the patient was diagnosed with B-cell ALL at 6 months of age and relapsed for the second time following repeat allogeneic HSCT (one after first CR [CR1] and the other after CR2).  During blinatumomab monotherapy, he developed an extra-medullary relapse.  Finally, the combined therapy with clofarabine, DLI, and blinatumomab induced CR of the bone marrow and extra-medullary relapse.  Unfortunately, the patient developed CNS relapse, however, this case showed a promising potential for combination therapy with clofarabine, DLI, and blinatumomab in r/r B-cell ALL.

Melanoma

Neubauer (2017) noted that the newest weapon in cancer therapy is checkpoint inhibition, which is the result of basic immunology research.  The success of this therapy is based on the fact that upon light microscopy, many solid tumors harbor lymphocytic cells infiltrating the tumor (TILs), and in many solid tumors, the presence of these TILs are prognostic.  Ipilimumab was the first MAb developed against a target present on T cells after becoming activated, CTLA-4.  In malignant melanoma, ipilimumab showed its beneficial effect as compared to a placebo peptide . However, the therapy with this antibody harbors significant toxicity.  Meanwhile, other targets such as PD-1, also expressed on (late) activated T cells, were identified, and therapies with antibodies inhibiting PD-1/PD-L1 are less toxic.  Although these antibodies show response only in a minority of patients, the benefit appeared durable in some of these patients.  In solid tumors such as melanoma or non-small cell lung cancer (NSCLC), treatment with PD-1 inhibitors has resulted in a significant prolongation of survival, even in first-line treatment.  As these drugs have been approved for many indications, it is important to know the drugs and side effects.   Resistance towards these drugs are caused by low expression of the natural ligand, PD-L1, in the tumor tissue, as well as acquired loss of signal transduction of interferon-related genes such as JAK1 or JAK2, respectively.  Also new in cancer therapy are BiTEs such as blinatumomab, and autologous chimeric antigen receptor-modified T cells (CAR-Ts).

Non-Hodgkin’s Lymphomas (e.g., Burkitt Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma)

Oak and Bartlett (2015) stated that blinatumomab is a bi-specific T-cell engager (BiTE) molecule that recruits cytotoxic T cells to target tumor B cells by linking the CD3 and CD19 antigens.  Among the various formats of bi-specific antibodies developed in the past 50 years, the BiTE class is remarkable for its low effector-to-target ratio, high tissue penetration and singular ability to activate T cells independent of MHC class I presentation or co-stimulation.  Blinatumomab has been studied in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) and B-precursor acute lymphoblastic leukemia (B-ALL).  These researchers reviewed the current literature on blinatumomab including its pharmacology, pre-clinical findings, clinical trials in B-cell NHL; and to a lesser extent, phase II studies in B-ALL.  These investigators discussed the potential future directions in light of other new competing therapies for NHL and unmet clinical needs in the market.  The authors concluded that the recent approval of blinatumomab for B-ALL symbolizes a breakthrough for BiTE technology with prospective application in the targeted therapy of other cancers.  They stated that although blinatumomab seems an unlikely option for treating indolent lymphoma due to toxicity, the need for long-term continuous infusion therapy and multiple promising well-tolerated oral agents, it holds promise for aggressive NHL patients whose diseases are refractory to current standard approaches.  They stated that larger trials are needed to demonstrate blinatumomab's curative potential in aggressive histologies.

Dozzo and associates (2016) noted that Burkitt lymphoma (BL) is an aggressive B-cell neoplasm displaying highly characteristic clinico-diagnostic features, the biologic hallmark of which is a translocation involving immunoglobulin and c-MYC genes.  It presents as sporadic, endemic, or epidemic disease.  Endemicity is pathogenetically linked to an imbalance of the immune system that occurs in African children infected by malaria parasites and Epstein-Barr virus (EBV), while the epidemic form strictly follows the pattern of infection by HIV.  These investigators stated that approximately 50 % of all BL patients are younger than 40 years, and 1/3 belong to the adolescent and young adult (AYA) subset, defined by an age between 15 and 25 to 40 years, based on selection criteria used in different reports.  Burkitt lymphoma shows propensity to extra-nodal involvement of abdominal organs, bone marrow, and central nervous system (CNS), and can cause severe metabolic and renal impairment.  Nevertheless, BL is highly responsive to specifically designed short-intensive, rotational multi-agent chemotherapy programs, empowered by the anti-CD20 monoclonal antibody (MAb) rituximab.  When carefully applied with appropriate supportive measures, these modern programs achieved a cure rate of approximately 90 % in the average AYA patient, irrespective of clinical stage, which is the best result achievable in any aggressive lymphoid malignancy to-date.  The challenges ahead concern the following: optimization of management in under-developed countries, with reduction of diagnostic and referral-for-care intervals, and the applicability of currently curative regimens; the development of lower intensity but equally effective treatments for frail or immunocompromised patients at risk of death by complications; the identification of very high-risk patients through positron-emission tomography (PET) and MRD assays; and the assessment in these and the few refractory/relapsed (r/r) ones of new MAbs (e.g., ofatumumab, blinatumomab, inotuzumab ozogamicin) and new molecules targeting c-MYC and key proliferative steps of B-cell malignancies.

Viardot and colleagues (2016) stated that few patients with r/r diffuse large B-cell lymphoma (DLBCL) attained prolonged disease-free survival (DFS).  In a phase II clinical trial, these researchers evaluated step-wise (9 to 28 to 112 μg/day with weekly dose increases; n = 23) or flat (112 μg/day; n = 2) dosing of blinatumomab by continuous infusion, with dexamethasone prophylaxis, in patients with r/r DLBCL.  Patients received a median of 3 prior lines of therapy.  Median time since last regimen was 1.5 months; 17 patients ended treatment in cycle 1 (induction), 7 in cycle 2 (consolidation), and 1 in re-treatment.  Among 21 evaluable patients, the overall response rate (ORR) after 1 blinatumomab cycle was 43 %, including CRs in 19 %; 3 patients had late CR in follow-up without other treatment.  The most common adverse events (AEs) with step-wise dosing were tremor (48 %), pyrexia (44 %), fatigue (26 %), and edema (26 %).  Grade 3 neurologic events with step-wise dosing were encephalopathy and aphasia (each 9 %) and tremor, speech disorder, dizziness, somnolence, and disorientation (each 4 %).  Of 5 (22 %) patients who discontinued step-wise dosing because of AEs, 4 (17 %) had neurologic events; most neurologic events resolved.  The flat-dose cohort was stopped because of grade 3 neurologic events in both patients.  The authors concluded that blinatumomab monotherapy appeared effective in patients with r/r DLBCL, a heavily pre-treated patient population with a high unmet medical need.  Moreover, they stated that future strategies for blinatumomab therapy to optimize the balance of efficacy and tolerability in r/r DLBCL may include modified dose schedules that provide the target dose earlier in the course of therapy, a better understanding of minimum treatment duration necessary to achieve responses, or using blinatumomab as consolidation therapy after initial "debulking".

Anastasia and Rossi (2016) noted that follicular lymphoma(FL) is the most common indolent NHL and constitutes 15 % to 30 % of lymphoma diagnoses.  The natural history of the disease is characterized by recurrent relapses and progressively shorter remissions with a median survival of 10 years.  The impossibility of achieving a definite cure, have prompted investigations into the possible role of more active and less toxic strategies with innovative therapeutic agents.  Recently research demonstrated that approximately 20 % of patients with FL relapse within 2 years after achieving remission with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and have a poor prognosis.  It is conceivable that this particularly chemo-resistant population would benefit from specifically targeting the biologic and genetic factors that likely contribute to their poor prognosis.  Evolving strategies for difficult to treat FL patients have recently considered immunomodulatory agents, new MAbs as well as drugs targeting selective intra-cellular pathways.  The importance of targeting the micro-environment together with the malignant FL cell has been particularly underscored.  These investigators reviewed the most promising approaches, such as combining anti-CD20 antibodies with immunomodulatory drugs (lenalidomide), MAbs directed against other surface antigens such as CD22 and CD23 (epratuzumab, lumiliximab), immunomodulatory antibodies such as PD-1, or inhibitors of key steps in the B-cell receptor pathway signaling such as PI3K inhibitors (idelalisib, duvelisib).  Another highly attractive approach is the application of the BiTE antibody blinatumomab that targets both CD19 and CD3 antigens.  The authors highlighted the potential of these therapies, taking into account their toxicity; results of phase III trials are awaited to confirm the benefit of these new therapeutic strategies toward a new era of chemotherapy-free treatment for FL.

Bukhari and Lee (2019) stated that blinatumomab is a member of a novel class of bi-specific antibody constructs with dual binding specificities.  While its primary clinical use has been in B-cell ALL, its role in the treatment of B-cell NHL (B-NHL) is less well established.  These investigators provided a brief overview of the market, unmet needs, and how blinatumomab fits in to the evolving armamentarium of lymphoma-directed therapies.  They addressed its therapeutic role in salvage therapy for r/r NHL, as consolidation for high-risk DLBCL following ASCT, and through various combinations with other available agents.  Moreover, these researchers highlighted key competitors.  The authors concluded that although blinatumomab showed impressive results in phase-I and phase-II clinical trials for r/r DLBCL, its future utility remains to be seen in this clinical setting due to lack of phase-III clinical trial and FDA approval of CD19 CART therapy.  A new CD19/CD3 and several CD20/CD3 bi-specific antibodies with longer half-life and resultant easier mode of administration that can overcome the major barriers of its use in clinical practice are in the pipeline and their role in NHL treatment are actively examined.

In an open-label, phase-II clinical trial, Coyle and colleagues (2020) examined the safety and efficacy of blinatumomab as second salvage for aggressive r/r B-NHL following platinum-based first salvage chemotherapy.  A total of 41 patients with aggressive disease (32 % relapsed; 68 % refractory) enrolled and received step-wise blinatumomab (9-28-112 μg/day) in a 70-day cycle 1 and an optional 28-day cycle 2; 19 (46 %) completed cycle 1 and 3 (7 %) completed cycle 2 . The ORR after 12 weeks was 37 %, including 9 (22 %) complete metabolic responses; 8 (20 %) patients (all responders) subsequently received HSCTs.  Grade greater than or equal to 3 AEs were reported in 29 (71 %) patients.  Grade-3 CRS occurred in 1 patient.  Grade-3 neurologic events occurred in 10 (24 %) patients; all resolved.  The authors concluded that blinatumomab monotherapy appeared effective as second salvage therapy in patients with r/r aggressive B-NHL.  These researchers stated that these findings implied a potential for effective use of blinatumomab earlier in the salvage treatment continuum and raise the question of whether efficacy could be improved in combination with other conventional or experimental therapies; however, additional investigation is needed.

The authors concluded that this study was limited by a relatively high rate of treatment discontinuation during the first treatment cycle, primarily due to disease progression (n = 17) rather than to AEs (n = 4).  Overall, 46 % of patients completed cycle 1 and 7 % completed the optional cycle 2.  Consequently, exposure to blinatumomab was lower than anticipated, with 34 % of patients receiving less than 50 % of the intended dose, and only 59 % receiving greater than or equal to 80 % of the intended dose.  Although at least 1 week of treatment at the target dose of 112 μg/day appeared necessary for efficacy examining other dosing strategies may be appropriate.  Despite this limitation, the ORR and complete metabolic response (CMR) rates observed with blinatumomab were encouraging given the aggressive nature of heavily pretreated r/r disease in this population of patients.  The longer follow-up period at the final analysis will allow for better estimation of the effects of blinatumomab on OS and relapse-free survival (RFS) in this cohort.

Appendix

Table: Examples of Tyrosine Kinase Inhibitors (TKIs)

Generic Name	Brand Name
bosutinib	Bosulif
crizotinib	Xalkori
dasatinib	Sprycel
erlotinib	Tarceva
imatinib	Gleevec
lapatinib	Tykerb
nilotinib	Tasigna
sorafenib	Nexavar
sunitinib	Sutent

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 "+" :
Blinatumomab (Blincyto) :
Other CPT codes related to the CPB:
38242	Allogeneic lymphocyte infusions
96413 - 96417	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J9039	Injection, blinatumomab, 1 mcg
ICD-10 codes covered if selection criteria are met:
C91.00	Acute lymphoblastic leukemia not having achieved remission
C91.01	Acute lymphoblastic leukemia, in remission
C91.02	Acute lymphoblastic leukemia, in relapse
ICD-10 codes not covered for indications listed in the CPB:
C43.0 - C43.9	Malignant melanoma of skin
C82.00 - C82.99	Follicular lymphoma
C83.30 - C83.39	Diffuse large B-cell lymphoma
C83.70 - C83.79	Burkitt lymphoma
C85.10 - C85.99	Non-Hodgkin lymphoma
C92.00 - C92.02	Acute myeloblastic leukemia
C92.90 - C92.92	Myeloid leukemia, unspecified [acute]
C95.00 - C95.02	Acute leukemia of unspecified cell type

The above policy is based on the following references: