Inotuzumab Ozogamicin (Besponsa)

Number: 0919

Policy

Note: REQUIRES PRECERTIFICATIONFootnotes*

1. Aetna considers inotuzumab ozogamicin (Besponsa) medically necessary for the treatment of adults (18 years of age or older) with relapsed or refractory CD22 positive (i.e., greater than or equal to 5% blasts CD22-positive) B-cell precursor acute lymphoblastic leukemia (B-ALL) when either of the following criteria is met:

1. Member has Philadelphia chromosome-positive (Ph+) disease and is intolerant or refractory to tyrosine kinase inhibitors (e.g., imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasygna), bosutinib (Bosulif), ponatinib (Inclusig)) and standard chemotherapy; or
2. Member has Philadelphia chromosome-negative (Ph-) disease.

2. Aetna considers inotuzumab ozogamicin experimental and investigational for non-Hodgkin lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, indolent lymphoma, and mantle cell lymphoma), and all other indications..

Footnotes* Precertification of inotuzumab ozogamicin (Besponsa) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of inotuzumab ozogamicin, call (866) 503-0857, or fax (866) 267-3277.

Background

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).

The National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium (2018) states that inotuzumab ozogamicin is recommended as a single-agent therapy for relapsed/refractory Philadelphia chromosome-positive B-ALL in TKI intolerant/refractory patients (category 2A), and as a single agent for relapsed/refractory Philadelphia chromosome-negative B-ALL (category 1).

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.

Appendix

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. 

Recommended dosing according to FDA-approved labeling (Pfizer, 2017) is as follows:

• Pre-medicate with corticosteroid, antipyretic, and antihistamine prior to all infusions.
• For the first cycle: total dose for all adult patients 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 patient achieves a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity.
     
• Subsequent cycles: In patients 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; or
• In patients 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. Patients who do not achieve a CR or CRi within 3 cycles should discontinue treatment.
• For patients proceeding to hematopoietic stem cell transplant (HSCT), the recommended duration of treatment is 2 cycles. A third cycle may be considered for those patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after 2 cycles.
• For patients not proceeding to HSCT, additional cycles of treatment, up to a maximum of 6 cycles, may be administered.
  
  

The above policy is based on the following references: