FLAG with Bortezomib in Children and Adolescents with Relapsed/Refractory Acute Myeloid Leukemia in a Resource-Limited Setting: A Single-Center Experience from India

Abstract

Objectives

The present study aimed to evaluate the impact, challenges, and outcome by adding bortezomib to the FLAG (fludarabine, cytarabine, and filgrastim) regimen in these populations in a resource-constraint setting.

Materials and Methods

A prospective observational study was conducted at a tertiary cancer center in India from January 2022 to September 2024 involving patients diagnosed with relapsed/refractory acute myeloid leukemia (AML) receiving FLAG-bortezomib. Complete remission (CR) and associated toxicities were assessed.

Results

Out of 13 patients, 8 (61.53%) were males and 5 (38.46%) were females (range: 2–17 years). Sorafenib (n = 1) and midostaurin (n = 2) were given along with chemotherapy for children with FLT3 mutations. Myelosuppression was the most frequent toxicity, with all patients developing ≥ grade 3 pancytopenia. Five (38.46%) patients achieved CR after first cycle, two (15.39%) died during treatment, and six (46.15%) were with persistent leukemic activity. Median duration of neutrophil and platelet recovery was 22 (range: 6–65) and 24 (range: 5–70) days, respectively, in children who achieved CR. Median overall survival was 12 months. At the last follow-up, three (23.08%) patients are alive.

Conclusion

FLAG-bortezomib regimen could help in pediatric and adolescent relapsed AML to achieve a remission comparable with other regimen in low- and middle-income countries, highlighting its potential.

 

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Keywords

FLAG-bortezomib - pediatric AML - pediatric oncology - relapsed/refractory AML - salvage chemotherapy of relapsed AML

Maharshi Trivedi

Introduction

FLAG (fludarabine, cytarabine, and filgrastim) regimen is utilized extensively for relapsed acute myeloid leukemia (AML) with or without idarubicin to enhance the outcome.[1] However, it has been observed that combination of FLAG-idarubicin has been associated with significant toxicity.[2] Bortezomib is a proteasome inhibitor and has been shown in preclinical and clinical studies that it is active against myeloid leukemia cells.[3] Bortezomib has better toxicity profile compared with anthracyclines and is used in salvage regimen.[3] There are few studies reporting the use of bortezomib in relapsed/refractory AML to eschew the toxicities associated with anthracycline. Thus, the target endpoint of the present study was the remission status and associated toxicities after the first cycle of salvage chemotherapy with FLAG-bortezomib in a resource-limited setting.

 

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Material and Methods

A prospective observational study was conducted from January 2022 to September 2024 at a tertiary cancer center in the western part of India. Pediatric and adolescent patients aged ≤ 18 years with relapsed/refractory AML were recruited. Institutional ethical committee permission was obtained prior to conducting the study (IRC/61/2022).

Fludarabine was infused daily on days 2 to 6 at 30 mg/m² intravenous infusion over 4 hours. Cytarabine was dispensed intravenously at 2 g/m² over 4 hours on days 2 to 6. Granulocyte-stimulating factor was administered at 0.5 µg/kg/day via subcutaneously from days 1 to 7. Bortezomib was delivered at a dose of 1.3 mg/m² as an intravenous bolus push on days 1, 4, 8, and 11. Sorafenib was given at a dose of 200 mg/m² once daily orally or midostaurin at a dose of 30 mg/m² twice daily for 14 days depending on availability; starting from day 8 was also given to children with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation. All the patients received prophylactic antiviral, antifungal, and antipneumocystis medications during the treatment course.

Response assessment was done by bone marrow examination to document morphological remission when absolute neutrophil counts were ≥ 1000/cumm and platelets were > 80 × 10⁹/L without support or on post-chemo day +35 in case of incomplete count recovery.

Statistical analysis in the present study was performed using SPSS software version 22 (IBM Corp., Armonk, United States). Complete remission (CR) was defined as morphological remission in the bone marrow examination with neutrophil counts ≥ 1000/cumm and platelets > 80 × 10⁹/L.

 

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Results

Thirteen patients received FLAG-bortezomib as reinduction regimen in our study. Eight (61.53%) were males and five (38.46%) were females, with a median (range) age of 12 years (range: 2–17 years). Median range of white blood cell at the start of the cycle was 22,648/μL (range: 900–107,000/μL). Five (38.46%) patients relapsed with a median interval of 5 months (range: 2–10 months) post-first-line chemotherapy, and eight (61.53%) were refractory post-first induction chemotherapy. Five patients had FLT3 mutations at relapse, three with FLT3-ITD and two with FLT3-tyrosine kinase domain (TKD) mutation. Additionally, each patient had CEBPA, GATA2, and FANCG mutation. Two patients had trisomy 8, and one had RUNX1-RUNXT1 translocation. Targeted therapy for FLT3 mutation with sorafenib in one (7.69%) patient and midostaurin in two (15.38%) patients were given.

Out of 13 patients, 5 (38.46%) achieved morphological remission post-reinduction treatment, 6 (46.15%) patients had persistent leukemic activity (PLA) after first cycle, and 2 (15.39%) died during reinduction treatment. Out of five (38.46%) children who achieved morphological remission, all received consolidation chemotherapy. Reasons for not consolidating with hematopoietic stem cell transplant in these patients were parental refusal, financial constraints, and/ or lack of social support for transplant/posttransplant care. At a median follow-up duration of 12 months, three (23.08%) patients are alive, all are in remission (two after FLAG-bortezomib and one after second salvage chemotherapy). Three patients relapsed after achieving remission and out of them one received second salvage chemotherapy and two opted for best supportive care, all died due to the disease. Out of six (46.15%) children who had PLA at the end of reinduction treatment, three opted for supportive care and three received second reinduction treatment with alternate regimen, one child is alive without evidence of disease. [Table 1] highlights the demographic, clinical details, and outcome of relapsed AML children treated FLAG-bortezomib.

Table 1 Demographic and clinical details of relapsed AML children receiving FLAG-bortezomib

Patient no.	Age (year)/sex	Relapsed/refractory	Molecular/cytogenetic abnormalities	Relapsed/refractory site: BM only/EM only/BM + EM	Status on completion of FLAG-bortezomib	Status at last follow-up
1	11/M	Refractory	−	BM only	Complete remission	Alive in remission
2[a]	15/M	Refractory	FLT3-ITD	BM + EM	PLA	Death
3	12/M	Relapsed	RUNX1- RUNX1T1	BM only	Death	Death
4	8/M	Refractory	FANCG	BM only	Death	Death
5	14/M	Relapsed	FLT3-ITD/ Trisomy 8	BM only	PLA	Death
6	13/F	Refractory	−	BM only	Complete remission	Death
7	2/M	Refractory	−	BM only	Complete remission	Death
8	4/F	Relapsed	CEBPA, GATA2	BM only	PLA	Death
9[b]	14/M	Refractory	FLT3-TKD	BM only	PLA	Death
10[a]	10/F	Refractory	FLT3-TKD	BM only	Complete remission	Death
11	17/F	Relapsed	Trisomy 8	BM only	PLA	Death
12	13/M	Refractory	−	BM only	Complete remission	Alive in remission
13	5/F	Relapsed	FLT3-ITD	BM only	PLA	Alive in remission

Abbreviations: AML, acute myeloid leukemia; BM, bone marrow; CEBPA, CCAAT enhancer binding protein alpha; EM, extramedullary; F, female; FLAG, fludarabine, cytarabine, and filgrastim; FLT3, FMS-like tyrosine kinase 3; ITD, internal tandem duplication; M, male; PLA, persistent leukemic activity; TKD, tyrosine kinase domain.

^a Received midostaurin + FLAG-bortezomib.

^b Received sorafenib + FLAG-bortezomib.

Two (15.39%) children succumbed to death during reinduction treatment with FLAG-bortezomib. Myelosuppression was the most documented toxicity, with all patients having ≥ grade 3 pancytopenia. Median duration of neutrophil recovery and platelet recovery were 22 days (range: 6–65 days) and 24 days (range: 5–70 days), respectively, in children who achieved remission. Median hospital admission duration was 48 days (range: 19–86 days). Other side effects were enterocolitis (n = 5, 38.46%), lung infection (n = 3, 23.08%), sepsis (n = 3, 23.08%), hypokalemia (n = 7, 53.85%), hypoalbuminemia (n = 5, 38.46%), and elevated transaminases (n = 4, 30.77%). Bortezomib-related neuropathy was not found in any patients in the present study.

 

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Discussion

This study assessed the efficacy and safety of the FLAG-bortezomib regimen in children and adolescents with relapsed/refractory AML in a resource-poor environment. Our results show that FLAG-bortezomib has an acceptable CR rate that is on par with other FLAG-anthracycline-based regimens used in low- and middle-income countries (LMICs) with an acceptable level of associated toxicity.[4] This is especially important because the challenges are unique in LMICs, where access to novel therapies and comprehensive supportive care is often limited.

While survival rates for pediatric AML in high-income countries are over 70%, in LMICs, it is still dismal, with reported 5-year overall survival rates ranging from 30 to 60%.[5]

According to Horton et al, FLAG regimens with added bortezomib results in increased response rates without significantly increasing the toxicity, and therefore, an alternative in relapsed/refractory AML.[6] Our study findings support this and we could achieve CR in 38.46% after one cycle of FLAG-bortezomib. This is in line with other studies conducted by Yılmaz Bengoa et al, which showed a CR rate of 42%, and Cherulil et al who demonstrated a CR rate of 35%.[7] [8]

FLT3 mutations, particularly FLT3-ITD and FLT3-TKD, are associated with a poor prognosis in pediatric AML.[9] In our research, five patients carried FLT3 mutations and four showed PLA with FLAG-bortezomib therapy. We combined tyrosine kinase inhibitors along with a reinduction chemotherapy regimen for three children, and all children tolerated relatively well without any treatment-related deaths or increased morbidity.

Myelosuppression was the most common toxicity in our study, with all patients having ≥ grade 3 pancytopenia. Other toxicities documented include enterocolitis, lung infections, sepsis, hypokalemia, hypoalbuminemia, and elevated transaminases. Our study had a mortality of 15.39% from treatment-related complications, which is higher than the 8% reported by Cherulil et al and may reflect challenges faced in infection control and supportive care in resource-poor settings.[8]

This was a prospective observational study including a relatively fair number of patients at tertiary care centers in LMIC settings. We could also analyze molecular/cytogenetic abnormalities in our patients and we could also use targeted agents for a few of our patients. Limitations of the study are small sample size and short follow-up period. Future studies with a large population and extended follow-ups are required to validate these results.

 

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Conclusion

The FLAG-bortezomib regimen has significant potential as a salvage therapy for resource-poor settings in pediatric and adolescent relapsed/refractory AML. Although remission rates are encouraging, barriers still exist in the toxicities, supportive care, and access to transplantation. This approach needs further research in more sizeable cohorts as well as collaborative efforts toward the refining and validation process of the approach to ensure better outcomes in such a vulnerable population.

 

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Conflict of Interest

None declared.

Authors' Contributions

D.D., H.T., and M.T. contributed to the concept and design of the study, as well as the acquisition, analysis, and interpretation of data. The manuscript was drafted by D.D., M.T., R.Y., and C.D., along with participation in the critical review for important intellectual content. Supervision of the study was provided by M.T. and H.P.

Financial Disclosures

None.

• References

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Publikationsverlauf

Eingereicht: 14. Februar 2025

Angenommen: 18. April 2025

Artikel online veröffentlicht:
15. Mai 2025