Indication

Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia... Read More
Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

A prospective real-world study of Neulasta® Onpro®1,2

Header image for Real-world Evidence Studies page

In a prospective observational study of ~2600 cancer patients

Fewer patients experienced FN with Neulasta® Onpro® vs other FN-prophylaxis options1,2

Patient Group % of patients with FN across all cycles [95% CI] N Relative decrease in FN for Onpro®*

Other FN-prophylaxis options 9.4%
[7.51% - 11.21%]		 951 Chart: prospective study data
Neulasta® Onpro® received in all cycles 6.2%
[4.95% - 7.42%] 		1455

Other FN-prophylaxis options 9.4%
[7.51% - 11.21%]		 951 Chart: prospective study data
Neulasta® Onpro® received in first cycle† 6.4%
[5.21% - 7.59%] 		1624

This was an observational study and no formal statistical testing was performed. Descriptive statistics are available.

*Adjusted for baseline clinical and demographic differences between the groups, eg, degree of FN risk of chemotherapy regimen.

†Regardless of option received in subsequent cycles.

The primary endpoint was the overall incidence of FN over four cycles of chemotherapy, measured as ANC < 1000 x 106/L and one of the following occurring within 24 hours of decreased ANC: Temperature > 38°C, use of specific oral antibiotics (eg, ciprofloxacin, levofloxacin, moxifloxacin, amoxicillin-clavulante), or use of IV antibiotics.

FN = febrile neutropenia; ANC = absolute neutrophil count; CI = confidence interval; IV = intravenous.

Learn more about the first study of its kind, in which physicians chose their method of FN prophylaxis

 
 

In the first study of its kind, physicians chose the method of FN prophylaxis1,2

Illustration of study design

Illustration of study design

This was an observational study and no formal statistical testing was performed. Descriptive statistics are available.

The primary endpoint was the overall incidence of FN over four cycles of chemotherapy, measured as ANC < 1,000 x 106/L and one of the following occurring within 24 hours of decreased ANC: Temperature > 38°C, use of specific oral antibiotics (eg, ciprofloxacin, levofloxacin, moxifloxacin, amoxicillin-clavulante), or use of IV antibiotics.2

Investigators decided on the method of FN prophylaxis. Patients were grouped into either the Neulasta® Onpro® group or other FN-prophylaxis group based on FN-prophylaxis method received in the first cycle

  • – Other FN-prophylaxis options included Neulasta® PFS (20%), pegfilgrastim biosimilar PFS (41.7%), daily short-acting filgrastim or filgrastim biosimilar (7.3%), or no G-CSF (30.9%)
  • – In both groups, physicians could change their choice in subsequent cycles, but the method chosen in the first cycle was generally consistent over time

 

*Approximately 31% of patients did not receive G-CSF prophylaxis in cycle 1, and 24% did not receive G-CSF prophylaxis in any cycle.

FN = febrile neutropenia; G-CSF = granulocyte colony-stimulating factor; ANC = absolute neutrophil count; PFS = prefilled syringe.

In the same prospective observational study of ~2600 cancer patients

A lower frequency of FN occurred when Onpro® was used every cycle, at the right time

More patients received G-CSF support across every cycle with Neulasta® Onpro®
94% of patients who received Neulasta® Onpro® in the first cycle received a G-CSF across all cycles of chemotherapy.
Chart: every cycle G-CSF use in patients (%) Chart: every cycle G-CSF use in patients (%)
More patients received G-CSF support at the right time with Neulasta® Onpro®
95.5% of patients receiving Neulasta® Onpro® in every cycle received it on the day after chemotherapy.
Chart: delivery of G-CSF at the right time in patients (%) Chart: delivery of G-CSF at the right time in patients (%)

*Percent of patients receiving pegfilgrastim PFS on the day after chemotherapy, for all cycles in which pegfilgrastim PFS was administered.

Note regarding right-time delivery data: For any given patient, physicians generally chose the same FN-prevention therapy over time. However, a small percentage of patients received different therapies in different cycles. To facilitate comparison, the Onpro® group was comprised of patients who received Onpro® in every cycle. The comparator group was comprised of patients in the other physician-choice group who received pegfilgrastim PFS at least once, and measured patient compliance for only those cycles in which pegfilgrastim PFS was administered.

Study Design

Prospective observational US study to describe frequency of FN, adherence, and compliance among patients receiving myelosuppressive chemotherapy for breast, lung or prostate cancer or NHL.

  • The study enrolled patients from November 2018 to April 2020
  • The primary analysis included 2575 patients who completed up to four chemotherapy cycles
  • Investigators decided on the method of FN prophylaxis. Patients were grouped into either the Neulasta® Onpro® group or other FN-prophylaxis group based on FN-prophylaxis method received in the first cycle

    – Other FN-prophylaxis options included Neulasta® PFS (20%), pegfilgrastim biosimilar PFS (41.7%), daily short-acting filgrastim or filgrastim biosimilar (7.3%), or no G-CSF (30.9%)

    – In both groups, physicians could change their choice in subsequent cycles, but the method chosen in the first cycle was generally consistent over time

  • Secondary endpoints included: 1) Patients who received G-CSF support for all chemotherapy cycles regardless of timing of G-CSF administration (adherence) and 2) Patients who received pegfilgrastim on the day after chemotherapy in every cycle in which pegfilgrastim was administered (compliance)

Study Limitations

  • It was not possible to evaluate FN risk among patients lost to follow-up after study enrollment
  • Although the analysis of FN incidence controlled for known baseline differences between the groups, the lack of randomization means that the groups may have differed in ways that were not measured or recorded. The impact of such differences on the study findings is unknown
  • The study enrollment closed prematurely due to COVID-19 and did not achieve target sample sizes

Study Note

  • Of the 951 patients in the other FN-prophylaxis study arm, 228 (24%) did not receive G-CSF prophylaxis in any cycle. The rate of FN for the remaining 723 patients was 10.0%

PFS = prefilled syringe; NHL = non-Hodgkin’s lymphoma.

According to the National Comprehensive Cancer Network® (NCCN)

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend that pegfilgrastim be administered according to the FDA-approved dosing schedule (day after myelosuppresive chemotherapy)3,*

*NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Next-day Neulasta® helped significantly more patients to maintain their chemotherapy dosing and schedule
Chart: percent of patients who maintained relative dose intensity (RDI)

Dose intensity is defined as the delivered dose of chemotherapy per unit of time. RDI is expressed as a percentage, calculated as the delivered dose intensity divided by the standard dose intensity. A higher RDI is indicative of fewer dose reductions and delays. Patients with RDI ≥ 85% were considered to have maintained their dose. The 85% cut point is commonly reported in the literature.5

It was not possible to determine from the data whether Neulasta® patients received Onpro® or the prefilled syringe. However, of the 379 patients from these healthcare systems who received Neulasta® in the first cycle, 97% (n = 368) received it on the day following chemotherapy, as recommended in the Neulasta® Prescribing Information. The Neulasta® group in this analysis was limited to next-day patients.

Next-day Neulasta® reduces risk of FN and helped significantly more patients maintain RDI.
Unadjusted for clinical and demographic characteristics, patients were 98% more likely to maintain RDI (Odds Ratio = 1.98) over the course of chemotherapy vs no G-CSF4,*,†
Illustration of odds ratio calculation Illustration of odds ratio calculation
The odds ratio is the relationship of the next-day Neulasta® group’s odds to the No G-CSF group’s odds of maintaining RDI.
48% increase graphic; Odds Ratio = 1.48, p = 0.006‡
Adjusted for clinical and demographic characteristics, PATIENTS WERE 48% MORE LIKELY TO MAINTAIN RDI over the course of chemotherapy vs no G-CSF4,*,†

Study Design: Retrospective cohort study conducted at Geisinger Health System (Danville, PA), Henry Ford Health System (Detroit, MI), Kaiser Permanente Northwest (Portland, OR), and Reliant Medical Group (Worcester, MA), January 2009-December 2017 (for all sites except Geisinger, 2009-2014). Analysis included patients with breast cancer, colorectal cancer, lung cancer, or non-Hodgkin’s lymphoma, receiving chemotherapy regimens with high or intermediate risk of FN. Multivariable regression models were employed to estimate the relationship between the use of Neulasta® and RDI.

*RDI ≥ 85%.

†Course-level analysis. All cycles included. The analysis categorized patients as next-day Neulasta® users vs non-users of G-CSF based on the first cycle of chemotherapy only. However, for patients who received next-day Neulasta® in cycle 1, subsequent Neulasta® use was: 87% in cycle 2, 86% in cycle 3, and 78% in cycle 4. For patients who did not receive any G-CSF in cycle 1, no G-CSF use was 81% in cycle 2, 79% in cycle 3, and 79% in cycle 4.

‡Adjusted odds ratio controlling for clinical and demographic characteristics, including but not limited to age, metastasis (yes/no), and FN risk of chemotherapy regimen.

For reliable supply and a legacy of ongoing innovation, choose Neulasta® Onpro®

Explore reliability and innovation

Important Safety Information

Contraindication

  • Neulasta® (pegfilgrastim) is contraindicated in patients with a history of serious allergic reactions to pegfilgrastim or filgrastim
  • Reactions have included anaphylaxis

Splenic Rupture

  • Splenic rupture, including fatal cases, can occur following the administration of Neulasta®
  • Evaluate for an enlarged or ruptured spleen in patients who report left upper abdominal or shoulder pain

Acute Respiratory Distress Syndrome (ARDS)

  • ARDS has occurred in patients receiving Neulasta®
  • Evaluate patients who develop a fever and lung infiltrates or respiratory distress after receiving Neulasta®
  • Discontinue Neulasta® in patients with ARDS

Serious Allergic Reactions

  • Serious allergic reactions, including anaphylaxis can occur in patients receiving Neulasta®
  • Majority of events occurred upon initial exposure and can recur within days after discontinuation of initial anti-allergic treatment
  • Permanently discontinue Neulasta® in patients with serious allergic reactions

Allergies to Acrylics

  • On-body injector (OBI) for Neulasta® uses acrylic adhesives
  • Patients who are allergic to acrylic adhesives may have a significant reaction

Use in Patients With Sickle Cell Disorders

  • In patients with sickle cell trait or disease, severe and sometimes fatal sickle cell crises can occur in patients receiving Neulasta®
  • Discontinue Neulasta® if sickle cell crisis occurs

Glomerulonephritis

  • Has occurred in patients receiving Neulasta®
  • Diagnoses based on azotemia, hematuria, proteinuria, and renal biopsy
  • Generally events resolved after dose reduction or discontinuation of Neulasta®
  • If suspected, evaluate for cause and if cause is likely, consider dose-reduction or interruption of Neulasta®

Leukocytosis

  • Increased white blood cell counts of 100 x 109/L have been observed
  • Monitoring of complete blood count (CBC) during pegfilgrastim therapy is recommended

Thrombocytopenia

  • Thrombocytopenia has been reported in patients receiving pegfilgrastim. Monitor platelet counts

Capillary Leak Syndrome (CLS)

  • CLS has been reported after G-CSF administration, including Neulasta®
  • Characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration
  • Episodes vary in frequency, severity, and may be life-threatening if treatment is delayed
  • Patients with symptoms should be closely monitored and receive standard symptomatic treatment, which may include intensive care

Potential for Tumor Growth Stimulatory Effects on Malignant Cells

  • G-CSF receptor has been found on tumor cell lines
  • The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which Neulasta® is not approved, cannot be excluded

Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients With Breast and Lung Cancer

  • MDS and AML have been associated with the use of Neulasta® in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer. Monitor patients for signs and symptoms of MDS/AML in these settings

Potential Device Failures

  • Missed or partial doses have been reported in patients receiving pegfilgrastim via the on-body injector (OBI) due to the device not performing as intended
  • In the event of a missed or partial dose, patients may be at increased risk of events such as neutropenia, febrile neutropenia and/or infection than if the dose had been correctly delivered
  • Instruct patients to notify their healthcare professional immediately in order to determine the need for a replacement dose if they suspect that the device may not have performed as intended

Aortitis

  • Aortitis has been reported in patients receiving Neulasta®. It may occur as early as the first week after start of therapy
  • Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count)
  • Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue Neulasta® if aortitis is suspected

Nuclear Imaging

  • Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone imaging results

Most common adverse reactions

  • Bone pain
  • Pain in extremity

Please see Neulasta® full Prescribing Information.

Neulasta® Injection: 6 mg/0.6 mL in a single-dose prefilled syringe for manual use only.

Neulasta® Injection: 6 mg/0.6 mL in a single-dose prefilled syringe co-packaged with the on-body injector (OBI) for Neulasta® (Neulasta® Onpro® kit).

Special Instructions for the On-body Injector (OBI) for Neulasta®

A healthcare provider must fill the on-body injector (OBI) with Neulasta® using the co-packaged prefilled syringe and then apply the OBI to the patient’s skin (abdomen or back of arm). The back of the arm may only be used if there is a caregiver available to monitor the status of the OBI. Approximately 27 hours after the OBI is applied to the patient’s skin, Neulasta® will be delivered over approximately 45 minutes. A healthcare provider may initiate administration with the OBI on the same day as the administration of cytotoxic chemotherapy, as long as the OBI delivers Neulasta® no less than 24 hours after the administration of cytotoxic chemotherapy.

The prefilled syringe co-packaged in the Neulasta® Onpro® kit contains additional solution to compensate for liquid loss during delivery through the OBI. If this syringe is used for manual subcutaneous injection, the patient will receive an overdose. If the prefilled syringe for manual use is used with the OBI, the patient may receive less than the recommended dose.

Do not use the OBI to deliver any other drug product except the Neulasta® prefilled syringe co-packaged with the OBI. Use of the OBI has not been studied in pediatric patients.

The OBI should be applied to intact, non-irritated skin on the arm or abdomen.

A missed dose could occur due to an OBI failure or leakage. Instruct patients using the OBI to notify their healthcare professional immediately in order to determine the need for a replacement dose of pegfilgrastim if they suspect that the device may not have performed as intended. If the patient misses a dose, a new dose should be administered by single prefilled syringe for manual use as soon as possible after detection.

Review the Patient Information and Patient Instructions for Use with the patient and provide the instructions to the patient.

Refer to the Healthcare Provider Instructions for Use for the OBI for full administration information.

For any OBI problems, call Amgen at 1-800-772-6436 1-800-772-6436 or 1-844-MYNEULASTA (1-844-696-3852). 1-844-MYNEULASTA (1-844-696-3852).

References:
1. Yang BB, et al. Cancer Chemother Pharmacol. 2015;75:1199-1206. 2. Kirshner JJ, et al. Support Care Cancer. 2018;26:1323-1334. 3. Neulasta® (pegfilgrastim) Prescribing Information, Amgen. 4. Yang BB, et al. Clin Pharmacokinet. 2011;50:295-306. 5. Haegerstam GA. Acta Orthop Scand. 2001;72:308-317. 6. Schweizerhof M, et al. Nat Med. 2009;15:802-807.

References:
1. Data on file, Amgen; 2021. 2. Data on file, Amgen; 2020. 3.Weycker D, et al. J Oncol Pharm Pract. 2014;20:190-198. 4. Vogel CL, et al. J Clin Oncol. 2005;23:1178-1184.5. American Cancer Society. Watching for and Preventing Infections. https://www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/low-blood-counts/infections/preventing-infections-in-people-with-cancer.html. Accessed August 15, 2022. 6. Neulasta® (pegfilgrastim) Prescribing Information, Amgen.

References:
1. Data on file, Amgen; 2021. 2. Rifkin RM, et al. Support Care Cancer. 2022;1-10. doi: 10.1007/s00520-022-07226-9. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Myeloid Growth Factors V.1.2021. ©National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed April 5, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 4. Data on file, Amgen; 2020. 5. Lyman GH. J Natl Comr Canc Netw. 2009;7:2612-2615.

References:
1. Data on file, Amgen; [1]; 2022. 2. Data on file, Amgen; [2]; 2022.

References:
1. Data on file, Amgen; [1]; 2020. 2. Data on file, Amgen; [2]; 2020. 3. Data on file, Amgen; [3]; 2020. 4. Data on file, Amgen; 2016. 5. Vogel CL, et al. J Clin Oncol. 2005;23(6):1178-1184.

References:
1. Data on file, Amgen; 2021. 2. NEUPOGEN® (filgrastim) Prescribing Information, Amgen. 3. Neulasta® (pegfilgrastim) Prescribing Information, Amgen. 4. Data on file, Amgen; [1]; 2020. 5. Data on file, Amgen; [2]; 2020. 6. Data on file, Amgen; 2016. 7. Vogel CL, et al. J Clin Oncol. 2005;23(6):1178-1184. 8. Data on file, Amgen; [3]; 2020.

References:
1. Data on file, Amgen; [1]; 2020. 2. Data on file, Amgen; [2]; 2020. 3. Vogel CL, et al. J Clin Oncol. 2005;23(6):1178-1184. 4. Data on file, Amgen; 2021. 5. Rifkin RM, et al. Support Care Cancer. 2022;1-10. doi: 10.1007/s00520-022-07226-9. 6. Data on file, Amgen; 2022.

Back to top back-to-top

Important Safety Information

Contraindication

  • Neulasta® (pegfilgrastim) is contraindicated in patients with a history of serious allergic reactions to pegfilgrastim or filgrastim
  • Reactions have included anaphylaxis

Splenic Rupture

  • Splenic rupture, including fatal cases, can occur following the administration of Neulasta®
  • Evaluate for an enlarged or ruptured spleen in patients who report left upper abdominal or shoulder pain

Acute Respiratory Distress Syndrome (ARDS)

  • ARDS has occurred in patients receiving Neulasta®
  • Evaluate patients who develop a fever and lung infiltrates or respiratory distress after receiving Neulasta®
  • Discontinue Neulasta® in patients with ARDS

Serious Allergic Reactions

  • Serious allergic reactions, including anaphylaxis can occur in patients receiving Neulasta®
  • Majority of events occurred upon initial exposure and can recur within days after discontinuation of initial anti-allergic treatment
  • Permanently discontinue Neulasta® in patients with serious allergic reactions

Allergies to Acrylics

  • On-body injector (OBI) for Neulasta® uses acrylic adhesives
  • Patients who are allergic to acrylic adhesives may have a significant reaction

Use in Patients With Sickle Cell Disorders

  • In patients with sickle cell trait or disease, severe and sometimes fatal sickle cell crises can occur in patients receiving Neulasta®
  • Discontinue Neulasta® if sickle cell crisis occurs

Glomerulonephritis

  • Has occurred in patients receiving Neulasta®
  • Diagnoses based on azotemia, hematuria, proteinuria, and renal biopsy
  • Generally events resolved after dose reduction or discontinuation of Neulasta®
  • If suspected, evaluate for cause and if cause is likely, consider dose-reduction or interruption of Neulasta®

Leukocytosis

  • Increased white blood cell counts of 100 x 109/L have been observed
  • Monitoring of complete blood count (CBC) during pegfilgrastim therapy is recommended

Thrombocytopenia

  • Thrombocytopenia has been reported in patients receiving pegfilgrastim. Monitor platelet counts

Capillary Leak Syndrome (CLS)

  • CLS has been reported after G-CSF administration, including Neulasta®
  • Characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration
  • Episodes vary in frequency, severity, and may be life-threatening if treatment is delayed
  • Patients with symptoms should be closely monitored and receive standard symptomatic treatment, which may include intensive care

Potential for Tumor Growth Stimulatory Effects on Malignant Cells

  • G-CSF receptor has been found on tumor cell lines
  • The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which Neulasta® is not approved, cannot be excluded

Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients With Breast and Lung Cancer

  • MDS and AML have been associated with the use of Neulasta® in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer. Monitor patients for signs and symptoms of MDS/AML in these settings

Potential Device Failures

  • Missed or partial doses have been reported in patients receiving pegfilgrastim via the on-body injector (OBI) due to the device not performing as intended
  • In the event of a missed or partial dose, patients may be at increased risk of events such as neutropenia, febrile neutropenia and/or infection than if the dose had been correctly delivered
  • Instruct patients to notify their healthcare professional immediately in order to determine the need for a replacement dose if they suspect that the device may not have performed as intended

Aortitis

  • Aortitis has been reported in patients receiving Neulasta®. It may occur as early as the first week after start of therapy
  • Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count)
  • Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue Neulasta® if aortitis is suspected

Nuclear Imaging

  • Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone imaging results

Most common adverse reactions

  • Bone pain
  • Pain in extremity

Please see Neulasta® full Prescribing Information.

Neulasta® Injection: 6 mg/0.6 mL in a single-dose prefilled syringe for manual use only.

Neulasta® Injection: 6 mg/0.6 mL in a single-dose prefilled syringe co-packaged with the on-body injector (OBI) for Neulasta® (Neulasta® Onpro® kit).

Special Instructions for the On-body Injector (OBI) for Neulasta®

A healthcare provider must fill the on-body injector (OBI) with Neulasta® using the co-packaged prefilled syringe and then apply the OBI to the patient’s skin (abdomen or back of arm). The back of the arm may only be used if there is a caregiver available to monitor the status of the OBI. Approximately 27 hours after the OBI is applied to the patient’s skin, Neulasta® will be delivered over approximately 45 minutes. A healthcare provider may initiate administration with the OBI on the same day as the administration of cytotoxic chemotherapy, as long as the OBI delivers Neulasta® no less than 24 hours after the administration of cytotoxic chemotherapy.

The prefilled syringe co-packaged in the Neulasta® Onpro® kit contains additional solution to compensate for liquid loss during delivery through the OBI. If this syringe is used for manual subcutaneous injection, the patient will receive an overdose. If the prefilled syringe for manual use is used with the OBI, the patient may receive less than the recommended dose.

Do not use the OBI to deliver any other drug product except the Neulasta® prefilled syringe co-packaged with the OBI. Use of the OBI has not been studied in pediatric patients.

The OBI should be applied to intact, non-irritated skin on the arm or abdomen.

A missed dose could occur due to an OBI failure or leakage. Instruct patients using the OBI to notify their healthcare professional immediately in order to determine the need for a replacement dose of pegfilgrastim if they suspect that the device may not have performed as intended. If the patient misses a dose, a new dose should be administered by single prefilled syringe for manual use as soon as possible after detection.

Review the Patient Information and Patient Instructions for Use with the patient and provide the instructions to the patient.

Refer to the Healthcare Provider Instructions for Use for the OBI for full administration information.

For any OBI problems, call Amgen at 1-800-772-6436 1-800-772-6436 or 1-844-MYNEULASTA (1-844-696-3852). 1-844-MYNEULASTA (1-844-696-3852).