Inotuzumab Ozogamicin (Besponsa)

Number: 0919

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses inotuzumab ozogamicin (Besponsa) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of inotuzumab ozogamicin (Besponsa) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of inotuzumab ozogamicin (Besponsa), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   Aetna considers inotuzumab ozogamicin (Besponsa) medically necessary for the following indication:

   Acute lymphoblastic leukemia (ALL)

   1. For treatment of ALL as frontline (induction) therapy when all of the following criteria are met:

      1. Member has B-cell precursor ALL; and
      2. The tumor is CD22-positive as confirmed by testing or analysis to identify the CD22 protein on the surface of the B-cell; and
      3. Member has Philadelphia chromosome-negative disease; and
      4. The requested drug will be used in combination with cyclophosphamide, dexamethasone, vincristine, methotrexate and cytarabine with or without blinatumomab; and
      5. Member will not receive more than 6 treatment cycles of the requested drug;

   2. For treatment of ALL as consolidation therapy when all of the following criteria are met:

      1. Member has B-cell precursor ALL; and
      2. The tumor is CD22-positive as confirmed by testing or analysis to identify the CD22 protein on the surface of the B-cell; and
      3. Member meets one of the following:
         
         
         1. Member has Philadelphia chromosome-positive disease and the requested drug will be used in combination with a tyrosine kinase inhibitor (e.g., imatinib, dasatinib, nilotinib, bosutinib, ponatinib); or
         2. Member has Philadelphia chromosome-negative disease and meets one of the following criteria:
            
            
            1. The requested drug will be used as a single agent; or
            2. The requested drug will be used in combination with cyclophosphamide, dexamethasone, vincristine, methotrexate and cytarabine with or without blinatumomab; and

      4. Member will not receive more than 6 treatment cycles of the requested drug;

   3. For treatment of relapsed or refractory ALL when all of the following criteria are met:

      1. Member has B-cell precursor ALL; and
      2. The tumor is CD22-positive as confirmed by testing or analysis to identify the CD22 protein on the surface of the B-cell; and
      3. Member meets one of the following:
         
         
         1. Member has Philadelphia chromosome-positive disease; or
         2. Member has Philadelphia chromosome-negative disease; and

      4. The requested drug will be used in one of the following settings:

         1. As a single agent; or
         2. In combination with a tyrosine kinase inhibitor for Philadelphia chromosome-positive disease (e.g., bosutinib, dasatinib, imatinib, nilotinib, ponatinib); or
         3. In combination with cyclophosphamide, dexamethasone, vincristine, methotrexate and cytarabine with or without blinatumomab; and

      5. Member will not receive more than 6 treatment cycles of the requested drug.

   Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   Aetna considers continuation of inotuzumab ozogamicin (Besponsa) therapy (up to 6 cycles total) in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Inotuzumab ozogamicin (Besponsa) is available as 0.9 mg lyophilized powder in a single-dose vial for reconstitution and further dilution. The maximum time from reconstitution through the end of administration should be less than or equal to 8 hours, with less than or equal to 4 hours between reconstitution and dilution.

Acute Lymphoblastic Leukemia (ALL)

Recommended dosing according to FDA-approved labeling is as follows:

• Pre-medicate with corticosteroid, anti-pyretic, and anti-histamine prior to all infusions;
• For the first cycle: total dose for all adult individuals is 1.8 mg/m² per cycle, administered as 3 divided doses on Day 1 (0.8 mg/m²), Day 8 (0.5 mg/m²), and Day 15 (0.5 mg/m²)
  
  

  • Cycle 1 is 3 weeks in duration, but may be extended to 4 weeks if the individual achieves a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity;

• Subsequent cycles: In individuals who achieve CR or CRi, the recommended total dose of Besponsa is 1.5 mg/m² per cycle, administered as 3 divided doses on Day 1 (0.5 mg/m²), Day 8 (0.5 mg/m²), and Day 15 (0.5 mg/m²). Subsequent cycles are 4 weeks in duration; 
• In individuals who do not achieve a CR or CRi, the recommended total dose is 1.8 mg/m² per cycle given as 3 divided doses on Day 1 (0.8 mg/m²), Day 8 (0.5 mg/m²), and Day 15 (0.5 mg/m²). Subsequent cycles are 4 weeks in duration. Individuals who do not achieve a CR or CRi within 3 cycles should discontinue treatment.
• For individuals proceeding to hematopoietic stem cell transplant (HSCT), the recommended duration of treatment is 2 cycles.  A third cycle may be considered for individuals who do not achieve CR or CRi and minimal residual disease (MRD) negativity after 2 cycles;
• For individuals not proceeding to HSCT, additional cycles of treatment, up to a maximum of 6 cycles, may be administered.

Source: Wyeth Pharmaceuticals, 2018

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96401 - 96450	Chemotherapy administration
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366	each additional hour (List separately in addition to code for primary procedure)
HCPCS codes covered for indications listed in the CPB:
J9229	Injection, inotuzumab ozogamicin, 0.1 mg
Other HCPCS codes related to the CPB:
Bosutinib - no specific code
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1 mg
J8530	Cyclophosphamide; oral, 25 mg
J8540	Dexamethasone, oral, 0.25 mg
J8610	Methotrexate; oral, 2.5 mg
J9039	Injection, blinatumomab, 1 microgram
J9071	Injection, cyclophosphamide (auromedics), 5 mg
J9072	Injection, cyclophosphamide (dr. reddy's), 5 mg
J9073	Injection, cyclophosphamide (ingenus), 5 mg
J9074	Injection, cyclophosphamide (sandoz), 5 mg
J9075	Injection, cyclophosphamide, not otherwise specified, 5mg
J9076	Injection, cyclophosphamide (baxter), 5 mg
J9098	Injection, cytarabine liposome, 10 mg
J9100	Injection, cytarabine, 100 mg
J9255	Injection, methotrexate (accord) not therapeutically equivalent to J9260, 50 mg
J9260	Methotrexate sodium, 50 mg
J9370	Vincristine sulfate, 1 mg
ICD-10 codes covered if selection criteria are met:
C91.00	Acute lymphoblastic leukemia not having achieved remission [Philadelphia chromosome-positive precursor B-cell acute lymphoblastic leukemia (B-cell ALL), and for Philadelphia chromosome-negative B-cell ALL]
C91.01	Acute lymphoblastic leukemia, in remission
C91.02	Acute lymphoblastic leukemia, in relapse[Philadelphia chromosome-positive precursor B-cell acute lymphoblastic leukemia (B-cell ALL), and for Philadelphia chromosome-negative B-cell ALL]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C82.00 - C82.99	Follicular lymphoma
C83.10 - C83.19	Mantle cell lymphoma
C83.30 - C83.3A	Diffuse large B-cell lymphoma
C83.70 - C83.79	Burkitt lymphoma
C85.80 - C85.99	Non-Hodgkin lymphoma

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Background

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

• Besponsa is indicated for the treatment relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year and older.

Inotuzumab ozogamicin is available as Besponsa (Wyeth Pharmaceuticals, Inc.) and is a CD22-directed antibody-drug conjugate (ADC). N-acetyl-gamma-calicheamicin, a small molecule, is a cytotoxic agent that is covalently attached to the antibody. Cell cycle arrest and apoptic cell death is mediated by the binding of the ADC to CD22-expressing tumor cells, followed by internalization of the ADC-CD22 complex, and the intracellular release of N-acetyl-gamma-calicheamin dimethylhydrazide via hydrolytic cleavage of the linker (Wyeth Pharmaceutical, 2018).

Compendial Uses

• Pediatric acute lymphoblastic leukemia (ALL)
• ALL- frontline/consolidation therapy

Per the prescribing information, inotuzumab ozogamicin (Besponsa) carries the following boxed warnings:

• Hepatotoxicity, including hepatic veno-occlusive disease (VOD) (also known as sinusoidal obstruction syndrome): In the INO-VATE ALL trial, hepatoxicity, including severe, life-threatening and sometimes fatal hepatic VOD was noted in 14% (23/164) of patients in the Besponsa arm during or following treatment or following hematopoietic stem cell transplant (HSCT) after completion of treatment
• Increased risk of post-transplant non-relapse mortality: In the INO-VATE ALL trial, 48% (79/164) patients in the Besponsa arm and 22% (35/162) patients in the Investigator's choice of chemotherapy arm had a follow-up HSCT where the post-HSCT non-relapse mortality rate was 39% (31/79) and 23% (8/35) in the Besponsa arm compared to the Investigator's choice of chemotherapy arm, respectively.

Inotuzumab ozogamicin (Besponsa) carries the additional following warnings and precautions (Wyeth Pharmaceuticals, 2018):

• Myelosuppression: In the INO-VATE ALL trial, myelosuppression was noted in patients receiving Besponsa where thrombocytopenia and neutropenia were reported in 51% (83/164) and 49% (81/164) patients, respectively
• Infusion related reactions: In the INO-VATE ALL trial, infusion related reactions were noted in patients receiving Besponsa where 2% (4/164) patients reported infusion related reactions (all Grade 2)
• QT interval prolongation
• Embryo-fetal toxicity.

Per the prescribing information, the most common (≥20%) adverse reactions include thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.

Acute Lymphoblastic Leukemia

Acute lymphocytic leukemia (ALL) is an aggressive type of cancer that is characterized by the overproduction and accumulation of lymphoblasts in the bone marrow and blood, frequently accompanied by suppression of normal hematopoiesis (NIH, 2017). Precursor B cell acute lymphoblastic leukemia (precursor B-ALL), is postulated to arise from precursor B cells at varying stages of differentiation. The term precursor B-ALL is used if there are greater than 25 percent bone marrow blasts, with or without a mass lesion. Precursor B-ALL is more often associated with the poor-prognosis and survival rate in adults than childhood cases (Freedman, 2017). The majority of precursor B-cells are positive for cytoplasmic CD22 (Naeim, 2013). CD22 is a B-cell lineage differentiation antigen that has emerged as a leading therapeutic target in B cell malignancies (i.e. B-ALL) (Shah et al, 2015).

Kantarjian et al (2016) discussed their Pfizer funded INO-VATE ALL randomized phase 3 trial comparing inotuzumab ozogamicin with standard intensive chemotherapy for the treatment of adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-cell ALL). This open-label, international, multicenter study evaluated the safety and efficacy of inotuzumab ozogamicin compared with Investigator’s choice of chemotherapy in 326 adult patients. Eligible patients were ≥ 18 years of age (median, 47 years) with ≥5% bone marrow blasts on local morphologic analysis, CD22-positive, Philadelphia chromosome (Ph)–positive or Ph-negative ALL and were scheduled to receive their first or second salvage treatment. The two primary endpoints for this study were rates of complete remission (CR), including CR with incomplete hematologic recovery (Cri), and overall survival. The authors noted that the rate of CR was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval {CI}, 72.1 to 87.7] vs. 29.4% [95% CI, 21.0 to 38.8], P<0.001). Among the patients who had CR, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts) (78.4% vs. 28.1%, P<0.001); the duration of remission was longer in the inotuzumab ozogamicin group (median, 4.6 months [95% CI, 3.9 to 5.4] vs. 3.1 months [95% CI, 1.4 to 4.9]; hazard ratio, 0.55 [95% CI, 0.31 to 0.96]; P=0.03). In the survival analysis, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5.0 months [95% CI, 3.7 to 5.6] vs. 1.8 months [95% CI, 1.5 to 2.2]; hazard ratio, 0.45 [97.5% CI, 0.34 to 0.61]; P<0.001); the median overall survival was 7.7 months (95% CI, 6.0 to 9.2) versus 6.7 months (95% CI, 4.9 to 8.3), and the hazard ratio was 0.77 (97.5% CI, 0.58 to 1.03) (P=0.04). The rate of 2-year overall survival was 23% (95% CI, 16 to 30) in the inotuzumab ozogamicin group and 10% (95% CI, 5 to 16) in the standard-therapy group.” The only patients among whom remission rates did not differ significantly between the two treatment groups were those with Ph-positive or t(4;11)-positive ALL.

In August 2017, the U.S. Food and Drug Administration (FDA) approved Besponsa (inotuzumab ozogamicin), a CD22-directed antibody-drug conjugate (ADC), for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL) (FDA, 2017). FDA approval of inotuzumab ozogamicin was based on results from the Phase 3 INO-VATE ALL trial described above. All evaluable patients had B-cell precursor ALL that expressed CD22, with ≥ 90% of evaluable patients exhibiting ≥ 70% leukemic blast CD22 positivity prior to treatment (FDA, 2017). The FDA stated that all patients were required to have ≥ 5% bone marrow blasts and to have received 1 or 2 previous induction chemotherapy regimens for ALL. Patients with Philadelphia chromosome-positive B-cell precursor ALL were required to have disease that failed treatment with at least 1 tyrosine kinase inhibitor and standard chemotherapy (FDA, 2017).

The labeling for Besponsa includes a boxed warning for hepatotoxicity, including hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), and increased risk of post-HSCT non-relapse mortality (Pfizer, 2017). Veno-occlusive disease, including fatal and life-threating VOD, occurred in 14 percent of patients treated with inotuzumab ozogamicin. A higher post-HSCT non-relapse mortality rate occurred in patients treated with inotuzumab ozogamicin (39%) than chemotherapy (23%) (Pfizer, 2017).

In patients treated with inotuzumab ozogamicin, the most common (≥20%) adverse reactions were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, increased transaminases, abdominal pain, increased gamma-glutamyltransferase, and hyperbilirubinemia (Pfizer, 2017).

Inotuzumab Ozogamicin for the Treatment of Non-Hodgkin Lymphoma

In a phase-I clinical trial, Ogura and colleagues (2016) evaluated the safety, preliminary efficacy, and pharmacokinetics of inotuzumab ozogamicin in combination with the immunochemo-therapeutic regimen, rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), in patients with relapsed/refractory (R/R) CD22+ B-cell non-Hodgkin lymphoma (NHL).  In part 1 (n = 16), patients received inotuzumab ozogamicin plus R-CVP on a 21-day cycle with escalating doses of cyclophosphamide first then inotuzumab ozogamicin.  Part 2 (n = 10) confirmed the safety and tolerability of the maximum tolerated dose (MTD), which required a dose-limiting toxicity (DLT) rate of less than 33 % in cycle 1 and less than 33% of patients discontinuing before cycle 3 due to treatment-related adverse events (TRAEs).  Part 3 (n = 22) evaluated the preliminary efficacy of inotuzumab ozogamicin plus R-CVP.  The MTD was determined to be standard-dose R-CVP plus inotuzumab ozogamicin 0.8 mg/m2.  The most common treatment-related grade greater than or equal to 3 AEs in the MTD cohort (n = 38) were hematologic: neutropenia (74 %), thrombocytopenia (50 %), lymphopenia (42 %), and leukopenia (47 %).  Among the 48 patients treated in the study, 13 discontinued due to AEs, most commonly thrombocytopenia (n = 10).  Overall, 13 patients died, including 1 death due to treatment-related pneumonia secondary to neutropenia.  Among patients receiving the MTD (n = 38), the overall response rate (ORR) was 84 % (n = 32), including 24 % (n = 9) with CR; the ORR was 100 % for patients with indolent lymphoma (n = 27) and 57 % for those with aggressive histology lymphoma (n = 21).  The authors concluded that inotuzumab ozogamicin at 0.8 mg/m2 plus full dose R-CVP was associated with manageable toxicities and demonstrated a high rate of response in patients with R/R CD22+ B-cell NHL.  These investigators stated that although the anti-tumor activity of this combination was noteworthy, further investigation in a larger population are needed to determine whether this regimen offers an advantage over other previously established regimens or whether inotuzumab ozogamicin should be combined with other agents.

In a phase-II clinical trial, Goy and associates (2016) evaluated the safety and efficacy of inotuzumab ozogamicin (InO) in patients with indolent B-cell NHL refractory to rituximab alone, rituximab plus chemotherapy or anti-CD20 radio-immunotherapy.  Patients received InO 1.8 mg/m(2) intravenously on a 28-day cycle for a planned 4 to 8 cycles.  The initial InO dose and schedule could be adjusted for tolerability and patients were allowed to receive 2 additional cycles (up to 8 total) after achieving a CR.  The primary end-point was overall response.  A total of 81 patients were enrolled, among whom 48 (59 %) received greater than or equal to 3 InO cycles and 13 (16 %) completed the treatment phase.  The ORR was 67 % (CR, 31 %).  Median (95 % CI progression-free survival [PFS] was 12.7 (8.9 to 26.9) months; median overall survival (OS) was not reached.  Hematological AEs were common, particularly thrombocytopenia (74 %) and neutropenia (56 %).  These were also the most common AEs leading to treatment discontinuation (37 % and 11 %, respectively); 58%  of patients reported AEs leading to treatment discontinuation.  The authors concluded that InO demonstrated robust activity in these heavily pre-treated patients, although treatment duration was limited by hematological toxicities; additional studies may determine dosing regimens that allow for reduced toxicity.

In a phase-I clinical trial, Sangha and co-workers (2017) evaluated safety, tolerability, and preliminary activity of InO plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) in patients with R/R CD22+ B-cell NHL.  Patients received InO plus R-GDP (21-day cycle; 6-cycle maximum) using up-and-down dose-escalation schema for gemcitabine and cisplatin to define the highest dosage regimen(s) with acceptable toxicity (Part 1; n = 27).  Part 2 (n = 10) confirmed safety and tolerability; Part 3 (n = 18) evaluated preliminary efficacy.  Among 55 patients enrolled, 42 % were refractory at baseline (median 2 [range of 1 to 6] prior therapies); 38 % had diffuse large B-cell lymphoma (DLBCL).  The highest dosage regimen with acceptable toxicity was InO 0.8 mg/m2, rituximab 375 mg/m2, cisplatin 50 mg/m2, gemcitabine 500 mg/m2 (day 1 only) and dexamethasone 40 mg (days 1 to 4); this was confirmed in Part 2, in which 3 patients had DLTs (grade 4 thrombocytopenia [n = 2], febrile neutropenia [n = 2]).  Most frequent TRAEs were thrombocytopenia (any grade, 85 %; grade greater than or equal to 3, 75 %) and neutropenia (69 %; 62 %).  Overall, ORR was 53 % (11 CR, 18 partial responses [PR]); ORR was 71 %, 33 %, and 62 % in patients with follicular lymphoma (n = 14), DLBCL (n = 21), and mantle cell lymphoma (n = 13), respectively.  The authors concluded that inotuzumab ozogamicin 0.8 mg/m2 plus R-GDP was associated with manageable toxicity, although gemcitabine and cisplatin doses were lower than in the standard R-GDP regimen due to hematologic toxicity.  Evidence of anti-tumor activity was observed; however, these exploratory data should be interpreted with caution due to the small sample size and short follow-up duration.  These researchers noted that there are currently no plans for further investigation of InO plus R-GDP in NHL.  However, studies of InO in combination with other chemotherapeutics and/or other biologics are currently ongoing in order to better understand the potential benefit of combination therapies in patients with hematologic malignancies.

Dang and colleagues (2018) stated that InO demonstrated preliminary anti-tumor activity and manageable toxicity in phase-I/II clinical trials for the treatment of R/R B‐cell NHL (B-NHL), as a single‐agent and in combination with rituximab (R‐InO).  Given this preliminary evidence, a 2‐arm, randomized, open‐label, phase-III clinical trial was conducted to compare the safety and efficacy of R‐InO with investigator's choice (IC) of rituximab plus bendamustine (R‐B) or rituximab plus gemcitabine (R‐G), in adults with R/R CD20+/CD22+ aggressive B‐NHL who were not candidates for high‐dose chemotherapy (HDC), with or without transplant.  The primary end-point was OS; 2 interim analyses (IAs) were planned when 40 % and 70 % of OS events were reached.  The trial was to be terminated for futility if p > 0.29 [hazard ratio (HR) greater than 0.9] or p > 0.10 (HR > 0.82) at the 1st or 2nd IA, respectively, or if p < 0.0073 for efficacy at the 2nd analysis.  The planned IA based on approximately 40 % of OS events (108 events) conducted in May 2013 yielded an estimated HR of greater than 0.9 for OS in the R‐InO versus IC arm; enrollment was thus stopped for futility.  Reported here were the final data from this trial (locked on July 24, 2014) to inform future research and potential clinical studies in this difficult‐to‐treat patient population.  Patient enrollment occurred between February 2011 and May 2013; a total of 338 patients were randomized [R‐InO, n = 166; IC, n = 172 (R‐B, n = 137; R‐G, n = 35).  Nearly all patients (91 %) had DLBCL at baseline; 68 % were aged greater than or equal to 65 years.  Age was the primary reason why enrolled patients were not candidates for HDC (R‐InO, 77 %; IC, 67 %); 332 patients received greater than or equal to 1 dose of study drug [median (range) number of treatment cycles: 3.0 (1.0 to 6.0) for R‐InO and R‐G, 3.5 (1.0 to 6.0) for R‐B; 94 patients completed treatment.  Common reasons for discontinuing were progressive disease/relapse (R‐InO, 50 % versus IC, 57 %) and AEs (R‐InO, 32 % versus IC, 17 % ).  Median (range) duration of follow‐up among surviving patients was 14.9 (0.4 to 32.8) months for R‐InO and 15.9 (0.1 to 31.2) months for IC; OS was not significantly different for R‐InO versus IC (p = 0.708; HR [95 % CI: 1.1 [0.8 to 1.4] ); Kaplan-Meier estimated median (95 % CI OS was 9.5 (7.0 to 14.5) and 9.5 (7.7 to 14.1) months (estimated probabilities of OS [95 % CI] at 18 months, 35 % [27 to 43 %] and 37 % [29 to 45 %]); PFS was also not significantly different for R‐InO versus IC (p = 0.27; HR [95 % CI)] = 0.9 [0.7 to 1.2]).  Median (95 % CI) PFS with R‐InO and IC were 3.7 (2.9 to 5.0) and 3.5 (2.8 to 4.9) months (estimated probabilities of PFS [95 % CI] at 18 months, 19 % [13 to 26 %] and 17 % [12 to 24 %]).  Notably, survival among patients receiving R‐InO was prolonged for those with higher versus lower baseline CD22 expression levels.  Among all randomized patients, the ORR (95 % CI) was 41 % (33 to 49 %) for R‐InO and 44 % (36 to 51 %) for IC (arm difference, 3 % [−8 to 13 %]; p = 0·714); Kaplan-Meier estimated median (95 % CI) duration of response (DOR) for R‐InO versus IC was 11.6 (7.8 to not reached [NR]) versus 6.9 (5.5 to 10.8) months (HR = 0.76 [0.47 to 1.25]; p = 0.142).  Median OS and PFS with R‐InO were 9.5 [95 % CI: 7.0 to 14.5] and 3.7 [2.9 to 5.0] months, respectively; ORR and DOR were 41 % and 11.6 months.  Although comparisons across studies require caution due to differences in design and patient characteristics, median OS and PFS with R‐InO in the previous study with refractory aggressive B‐NHL (n = 30) were shorter (OS, 8.8 [3.9 to NR] months; PFS, 1.9 [1.0 to 4.8] months), the ORR was lower (20 %), and the DOR is shorter (6.1 months).  Conversely, the median OS and PFS with R‐InO in the relapsed DLBCL cohort in the previous study (n = 47) were longer (OS, NR [34.7 to NR] months; PFS, 17.1 [7.8 to NR] months), the ORR was higher (74 %), and the DOR was longer (17.7 months).

The authors concluded that rituximab‐InO treatment was associated with anti-tumor activity in patients with R/R aggressive B‐NHL who were not candidates for HDC, with or without transplant, for whom treatment options are limited.  However, R‐InO was not superior to IC with respect to OS; estimates of ORR and median PFS and OS were similar for the 2 treatments.  Nevertheless, the efficacy observed in this trial and in other studies suggested an examination of InO‐containing combination therapies may be appropriate in certain patient populations.  These researchers noted that a study of InO plus rituximab, cyclophosphamide, vincristine and prednisolone in chemotherapy‐naïve patients with DLBCL who are not candidates for anthracycline‐based treatment is currently recruiting.

Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy for the Treatment of Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Kantarjian and colleagues (2018) noted that inotuzumab ozogamicin has shown single-agent activity in relapsed or refractory ALL.  In a single-arm, phase-II clinical trial, these researchers examined the safety and activity of inotuzumab ozogamicin in combination with low-intensity chemotherapy in older patients with ALL.  Eligible patients were aged 60 years or older and had newly diagnosed, Philadelphia chromosome-negative, ALL, and an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or lower.  The induction chemotherapy regimen used was mini-hyper-CVD (a lower intensity version of the conventional hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, and dexamethasone]).  Odd-numbered cycles (1,3, 5, and 7) comprised intravenous cyclophosphamide (150 mg/m2 every 12 hours on days 1 to 3) and oral or intravenous dexamethasone (20 mg per day on days 1 to 4 and days 11 to 14); no anthracycline was administered.  Intravenous vincristine (2 mg flat dose) was given on days 1 and 8.  Even-numbered cycles comprised intravenous methotrexate (250 mg/m2 on day 1) and intravenous cytarabine (0.5 g/m2 given every 12 hours on days 2 and 3).  Intravenous inotuzumab ozogamicin was given on day 3 of the first 4 cycles at the dose of 1.3 to 1.8 mg/m2 at cycle 1, followed by 1.0  to 1.3 mg/m2 in subsequent cycles.  Maintenance therapy with dose-reduced POMP (purinethol [6-mercaptopurine], oncovin [vincristine sulfate], methotrexate, and prednisone) was given for 3 years.  The primary end-point of this study was PFS at 2 years.  Analyses were by intention-to-treat (ITT).  Between November 12, 2011, and April 22, 2017, a total of 52 patients with a median age of 68 years (inter-quartile range [IQR] 64 to 72) were enrolled.  With a median follow-up of 29 months (IQR 13 to 48), 2-year PFS was 59 % (95 % CI: 43 to 72).  The most frequent grade 3 to 4 AEs were prolonged thrombocytopenia (42 [81 %] patients), infections during induction (27 [52 %]) and consolidation chemotherapy (36 [69 %]), hyperglycemia (28 [54 %]), hypokalemia (16 [31 %]), increased aminotransferases (10 [19 %]), hyperbilirubinemia (9 [17 %]), and hemorrhage (7 [15 %]).  Veno-occlusive disease (VOD) occurred in 4 (8 %) patients; 6 (12 %) patients died from AEs that were deemed treatment related (5 [10 %] from sepsis and 1 [2 %] from VOD).  The authors concluded that inotuzumab ozogamicin plus mini-hyper-CVD chemotherapy was a safe and active 1st-line therapeutic option in older patients with newly diagnosed ALL and could represent a new therapy for this population.  These investigators stated that randomized, phase-III clinical trials to evaluate the efficacy of this combination compared with the current standard of care in this setting, combination chemotherapy without inotuzumab ozogamicin, are needed.

Jabbour and associates (2018) stated that the outcome of patients with R/R ALL is poor.  Inotuzumab ozogamicin has single-agent activity in R/R ALL.  In a single-arm, phase-II clinical trial, these researchers evaluated the safety and efficacy of inotuzumab ozogamicin plus low-intensity chemotherapy in patients with R/R ALL.  The chemotherapy used was lower intensity than hyper-CVAD and was referred to as mini-hyper-CVD (mini-HCVD: cyclophosphamide and dexamethasone at 50 % dose reduction, no anthracycline, methotrexate at 75 % dose reduction, and cytarabine at 0.5 g/m2 × 4 doses).  Inotuzumab was given on day 3 of the first 4 courses at 1.8 to 1.3 mg/m2 for cycle 1 followed by 1.3 to 1.0 mg/m2 for subsequent cycles.  The primary end-points were the ORR and OS; secondary end-points included safety, relapse-free survival (RFS), the rate of allogeneic stem cell transplantation (ASCT), and the minimal residual disease (MRD) negativity rate.  A total of 59 patients (30 women and 29 men) with a median age of 35 years (range of 18 to 87 years) were treated.  Overall, 46 patients (78 %) responded, 35 of them (59 %) achieving CR.  The overall MRD negativity rate among responders was 82 %; 26 patients (44 %) received ASCT.  Grade 3 to 4 toxic effects included prolonged thrombocytopenia (81 %; n = 48), infections (73 %; n = 43), and hyperbilirubinemia (14 %; n = 8); VOD occurred in 9 patients (15 %).  With a median follow-up of 24 months, the median RFS and OS were 8 and 11 months, respectively.  The 1-year RFS and OS rates were 40 % and 46 %, respectively.  The 1-year OS rates for patients treated in salvage 1, salvage 2, and salvage 3 or beyond were 57 %, 26 %, and 39 %, respectively (p = 0.03).  The authors concluded that the combination of inotuzumab ozogamicin with low-intensity mini-HCVD chemotherapy showed encouraging results in R/R ALL.  The risk of VOD should be considered carefully in patients with previous liver damage and among transplant candidates. 

The authors stated that this study was limited by its comparison with historical data; a randomized trial is therefore needed to confirm these findings.  In addition, the monthly inotuzumab ozogamicin regimen used in the present study may not be optimal -- there is evidence that weekly dosing of inotuzumab ozogamicin may result in lower rates of hepatic AEs and VOD.  A weekly regimen of inotuzumab ozogamicin in combination with low-intensity chemotherapy is currently being tested.

Inotuzumab and Blinatumomab Sequential Therapy for Relapsed/Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Ueda (2022) noted that to overcome the unfavorable outcome of R/R Philadelphia chromosome-positive ALL (Ph+ALL) and conduct allo-SCT safely, these researchers designed a sequential therapy involving a single cycle of inotuzumab ozogamicin (InO) and blinatumomab (Blina).  Two heavily treated and aged patients with R/R Ph+ALL were treated with the therapy.  Both of them achieved complete molecular remission without CRS and underwent allo-SCT without veno-occlusive disease/sinusoidal obstruction syndrome.  Although appropriate central nervous system (CNS) prophylaxis should be added, the InO-Blina sequential therapy is a promising strategy for treating R/R Ph+ALL as a bridging regimen before allo-SCT.  These investigators stated that this was a case report; a larger-scale clinical trial is needed to confirm the safety and effectiveness of InO-Blina sequential therapy.  The ongoing US Alliance for Clinical Trials in Oncology study A041703 for R/R Ph-negative ALL patients (clinicaltraials.gov ID #NCT03739814) would be helpful in this respect.

Inotuzumab and Bosutinib for Relapsed/Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Lymphoid Blast Phase of Chronic Myeloid Leukemia

Jain et al (2021) stated that R/R Ph+ALL and lymphoid blast phase of chronic myeloid leukemia (LBP-CML) have poor outcomes.  These researchers designed a phase-I/II clinical trial combining inotuzumab ozogamicin with bosutinib for this patient population; patients with T315I mutation were excluded.  Bosutinib was administered daily at 3 dose levels (300 mg/day, 400 mg/day, 500 mg/day) in a 3 + 3 design.  Inotuzumab ozogamicin was dosed weekly during cycle 1, and once every 4 weeks subsequently for a total of 6 cycles.  The primary objective was to determine the safety and the MTD of bosutinib in combination with inotuzumab ozogamicin.  A total of 18 patients were enrolled (Ph+ALL, n = 16; LBP-CML, n = 2).  The median age was 62 years (range of 19 to 74) and the median number of prior therapies was 1 (range of 1 to 5); DLTs included grade-3 skin rash and bosutinib 400 mg daily was determined as the MTD.  The most frequent grade 3/4 treatment-emergent AEs were thrombocytopenia (60 %) and neutropenia (38 %).  A CR / CR with incomplete count recovery (CRi) was achieved in 15/18 (83 %) patients; 11/18 (61 %) patients achieved negative MRD by flow cytometry.  Complete molecular response was noted in 10/18 (56 %) patients.  The 30-day mortality was 0 %.  After a median follow-up of 44 months, the median duration of response and OS were 7.7 months and 13.5 months, respectively; 6 patients had a subsequent allo-SCT.  No patient developed veno-occlusive disease.  The authors concluded that inotuzumab ozogamicin with bosutinib was well-tolerated in R/R Ph+ALL and LBP-CML.

Inotuzumab and Temsirolimus for Relapsed/Refractory CD22-Positive B-Cell Non-Hodgkin Lymphomas

In a phase-I clinical trial, Pirosa et al (2022) examined the safety, tolerability, and preliminary activity of inotuzumab ozogamicin in combination with temsirolimus in patients with R/R CD22 positive B-cell NHL.  A total of 19 patients received at least 1 dose of both study drugs; DLTs consisted of thrombocytopenia, hypertriglyceridemia, oral mucositis, clinical deterioration, and the inability to receive at least 3 doses of temsirolimus during cycle 1.  The most common grade greater than or equal to 3 treatment-related adverse events (AEs) were thrombocytopenia (n = 8), neutropenia (n = 5), and 2 patients each hyperphosphatemia, lymphopenia, and hypertriglyceridemia.  The recommended phase-II dose was inotuzumab ozogamicin 0.8 mg/m2 on day 1 in combination with temsirolimus 10 mg on days 8, 15, and 22 every 28 days.  Among 18 patients evaluable, 7 (39 %) with follicular lymphoma had a partial remission (PR).  The authors concluded that this drug combination was not possible within a therapeutically useful range of doses due to toxicities; anti-tumor activity was observed in heavily pre-treated patients

Treatment of Relapsed B-Cell Acute Lymphoblastic Leukemia

Wudhikarn et al (2022) stated that novel monoclonal antibody (mAb)-based therapies targeting CD19 and CD22 (blinatumomab and inotuzumab) have shown high rates of CR and been used as a bridging treatment to potentially curative allogeneic HSCT (allo-HSCT) in adults with relapsed or refractory (R/R) BB-ALL.  However, limited data exist on the outcome of patients resistant to both mAbs as well as responses to each agent when progressed after the alternate antigen-targeted mAb.  In a retrospective study, these investigators reported outcomes of 29 patients with R/R B-ALL previously treated with both blinatumomab and inotuzumab; 25 patients (86.2 %) received blinatumomab as 1st mAb (mAb1), and CD19-negative/dim relapses were observed in 44 % of the patients.  Inotuzumab induced CR in 68 % of the patients for post-blinatumomab relapse regardless of CD19 expression status.  The median time between mAb1 and mAb2 was 99 days; 12 (63.2 %) of 19 patients who achieved remission after mAb2 underwent allo-HSCT.  The median time from mAb2 to allo-HSCT was 37.5 days.  Acute graft-versus-host disease (GVHD) and non-relapse mortality were observed in 58.3 % (grade 3 or higher, 25 %) and 41.7 %, respectively.  With a median follow-up of 16.8 months after mAb2, 19 patients (65.5 %) relapsed, and 21 patients (72.4 %) have died; OS was not different between allo-HSCT and non-allo-HSCT patients.  The authors concluded that patients with B-ALL who relapsed after blinatumomab could be successfully rescued by inotuzumab as a bridge to allo-HSCT but represent an ultra-high-risk group with poor OS.  These researchers stated that further studies, including novel consolidation and treatment sequence, may improve outcomes of these patients.

The authors stated that the main drawbacks of this study were the small number of patients (n = 29), patient selection bias, and missing information due to the retrospective nature of the cohort.  The heterogeneity of salvage therapy, concomitant treatments, and allo-HSCT platforms could confound the interpretation of the study.  Data on MRD were not readily available in all patients; thus, potentially affecting the significance of results.  Lastly, because most patients in this trial received blinatumomab as the mAb1 followed by inotuzumab as the mAb2, the response pattern and toxicity profile following mAb2 in this cohort could be more representative of an effect of inotuzumab.

Mini-Hyper-CVD plus Inotuzumab, with or without Blinatumomab, in Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphocytic Leukemia

Jabbour et al (2023) noted that the outcome of older patients with B-cell acute lymphocytic leukemia is inferior to that in younger patients due to the adverse disease biology and their inability to tolerate intensive therapy.  In an open-label, phase-II clinical trial, these researchers examined the long-term outcomes of inotuzumab ozogamicin, with or without blinatumomab, in combination with low-intensity chemotherapy in these patients.  This trial enrolled patients aged 60 years or older with newly diagnosed, Philadelphia-chromosome negative, B-cell acute lymphocytic leukemia, and an ECOG performance status of 3 or lower.  This study was carried out at the University of Texas MD Anderson Cancer Center.  The induction chemotherapy consisted of mini-hyper-CVD and has been published before; inotuzumab ozogamicin was administered intravenously on day 3 of the first 4 cycles at a dose of 1.3 to 1.8 mg/m2 in cycle 1, followed by 1.0 to 1.3 mg/m2 in subsequent cycles (cycles 2 to 4).  Maintenance therapy with dose-reduced POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) was administered for 3 years.  From patient 50 onwards, the study protocol was amended to fractionate inotuzumab ozogamicin to a maximum cumulative dose of 2.7 mg/m2 (0.9 mg/m2 during cycle 1 fractionated into 0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1, and 0.6 mg/m2 in cycles 2 to 4 fractionated into 0.3 mg/m2 on day 2 and 0.3 mg/m2 on day 8) followed by blinatumomab for 4 cycles (cycles 5 to 8).  POMP maintenance was shortened to 12 cycles with 1 cycle of blinatumomab administered by continuous infusion after every 3 cycles of POMP.  The primary endpoint was PFS and was analyzed on an ITT basis.  This trial is registered with ClinicalTrials.gov (NCT01371630) and the data were from the newly diagnosed, older subgroup of patients treated on the phase-II portion of this trial; the trial is still enrolling patients.  Between November 11, 2011, and March 31, 2022, a total of 80 patients were enrolled and treated (32 women and 48 men; median age of 68 years [IQR 63 to 72]), 31 of whom were treated after the protocol amendment.  With a median follow-up of 92.8 months (IQR 8.8 to 67.4), the 2-year PFS was 58.2% (95 % CI: 46.7 to 68.2) and 5-year PFS was 44.0 % (31.2 to 54·3).  At a median follow-up of 104.4 months (IQR 6.6-89.2) for the patients treated before the protocol amendment and 29.7 months (8.8 to 41.0) for those treated after the protocol amendment, median PFS did not differ significantly between the 2 groups (34.7 months [95 % CI: 15.0 to 68.3] versus 56.4 months [11.3 to 69.7]; p = 0.77).  The most common grade-III to grade-IV events were thrombocytopenia in 62 (78 %) patients and febrile neutropenia in 26 (32 %) patients; 6 (8 %) patients developed hepatic sinusoidal obstruction syndrome.  There were 8 (10 %) deaths due to infectious complications, 9 (11 %) from complications related to secondary myeloid malignancy, and 4 (5 %) from sinusoidal obstruction syndrome.  The authors concluded that inotuzumab ozogamicin, with or without blinatumomab, added to low-intensity chemotherapy showed promising activity in terms of PFS in older patients with B-cell acute lymphocytic leukemia.  Moreover, these researchers stated that further attenuation of the chemotherapy regimen might improve tolerability while maintaining effectiveness in older patients.

Non-Hodgkin's Lymphoma

Amhaz et al (2022) stated that treatment of non-Hodgkin lymphoma (NHL) has improved over the years with the emergence of the monoclonal antibodies (MAB) therapy.  NHL is divided into B-cell NHL and T-cell NHL.  Treatment of NHL was based on the subtype of NHL and its staging.  NHL is divided into aggressive and indolent NHL (iNHL).  Subtypes of iNHL include follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia/small-cell lymphocytic lymphoma (CLL/SLL), gastric mucosa-associated lymphoid tissue (MALT) lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia (WM), nodal marginal zone lymphoma (NMZL), splenic marginal zone lymphoma (SMZL).  Chemotherapy was the main stay treatment of iNHL until the emergence of rituximab, anti-CD20 MAB targeting CD-20 surface cell antigens that are present on B-cells lymphoma and not on precursor cells, mainly effective in B-cell iNHL.  It became the mainstay treatment in FL as a single-agent modality or in combination with chemotherapy.  The anti-CD20 rituximab played an important role in the development of the treatment of iNHL and received FDA approval in 1997.  It was also proven effective in multiple other types of lymphoma.  MAB via targeting the cell surface antigen resulted in a direct or immune mediated cytotoxicity.  This carries few side effects, including allergic reactions.  Furthermore, these researchers noted that like rituximab, anti-CD22 was also tried in a conjugated form, linked to 90Y-ibritumomab tiuxetan and 131I-tositumomab to potentiate its activity in killing the lymphoma cells, yet this holds an increase in the potential side effects mainly severe myelosuppresion.  One radio-conjugated anti-CD20: 90Y-epratuzumab was studied in a clinical trial as a once-weekly infusion for 2 to 4 weeks to show a good ORR in both indolent and aggressive lymphoma patients, ORR was 75 % in iNHL.  Another important conjugated anti-CD22 is inotuzumab ozogamicin, an anti CD22 conjugated to an anti-tumor antibiotic calicheamicin, the data on this drug is mainly in B-cell acute lymphoblastic leukemia (B-ALL); however, there are data from a phase-I clinical trial in aggressive NHL and from pre-clinical data that reported promising findings to be further investigated; but not yet in iNHL.

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References