The results of the modified St Jude Total Therapy XV Protocol in the treatment of low- and middle-income children with acute lymphoblastic leukemia

Abstract

The St Jude Total Therapy Study XV was the first clinical trial to prospectively use minimal residual disease levels during and after remission induction therapy to guide risk-directed treatment. We used the Total Therapy XV protocol with minimal modification in treating 115 newly diagnosed pediatric acute lymphoblastic leukemia patients from low- and middle-income groups from January 2011 to December 2017. The mean age at diagnosis was 5.97 ± 3.96 years. The median follow-up period was 88 months. Three (2.6%) patients had bone marrow relapse, and one (0.87%) had an isolated central nervous system relapse. Nineteen of the patients (16.52%) died due to infection-related complications, three (2.61%) died due to progressive disease, and one (0.87%) died due to hematopoietic stem cell transplant complications. Five-year overall survival was 80%, and event-free survival was 78.3%. Our results showed that the Total XV treatment protocol could be used successfully in patients with ALL from low- and middle-income populations. However, infection-related deaths remain a significant problem.

Keywords:

• Lymphoid Leukemia
• infectious complications
• chemotherapeutic approaches

Acknowledgments

We thank Dr. Ching-Hon Pui MD, for reviewing the final version of this study and sharing his valuable comments with us. We also thank Prof Tayfur Toptas and Miss Imren Tatlı for their interpretation of the flow cytometry results.

Details of treatment plan

Treatment will consist of three main phases: (1) remission Induction, (2) consolidation, and (3) continuation.

All patients will receive IT therapy on day 1; dose is age dependent.

Upfront high-dose methotrexate window

HDMTX (1 g/m2) 24 h infusion. Leucovorin rescue will be given.

Remission induction

¥ Methylprednisolone 20 mg/kg/day PO Days 5–11, 10 mg/kg/day PO Days 12–18, 2 mg/kg/day PO Days 19–33

Vincristine 1.5 mg/m2/week IV Days 5, 12, 19, 26

Daunorubicin 25 mg/m2/week IV Days 5, 12

L-asparaginase 10,000 Unit/m2/dose IM Days 6, 8, 10, 12, 14, 16 (19, 21, 23; High risk patiens)

Cyclophosphamide 1000 mg/m2/dose IV Day 26

Cytarabine 75 mg/m2/dose IV Days 27–30, 34–37

6-Mercaptopurine 60 mg/m2/dose PO Days 26–39

Imatinib 40 mg/m2 bid for Ph positive patients starting Day 22 of induction.

Intrathecal therapy will be administered on day 1 and 19, dose age dependent. Patients with high risk of CNS relapse will receive additional IT treatments on days 8 and 26.

Consolidation treatment

High dose methotrexate targeted dose depending on risk status* and methotrexate serum levels€, days 1, 15, 29, and 43 and mercaptopurine 50 mg/m2/day, days 1–56.

*low-risk: 2.5 g/m2/24 h, standart and high-risk: 5 g/m2/24 h

€Methotrexate dose was adjusted according to the risk group in the first HD-MTX treatment block. In subsequent HD-MTX treatment blocks, drug doses were determined according to individual pharmacokinetics, taking into account the blood MTX levels measured in the first treatment block.

Reintensification treatment for patients with high risk disease:

Patients with high risk disease will be offered the option of hematopoietic stem cell transplant (HSCT) and may receive an additional 1–2 cycles of reintensification treatment prior to maximize the anti-leukemic kill before transplant.

Dexamethasone 20 mg/m2 PO days 1–3 Cytarabine 2 g/m2 IV x 4 doses, days 3–5 Etoposide 100 mg/m2 IV x 5 doses, days 3–5 L-asparaginase 25,000 Units/m2 IM day 6 Intrathecal treatment Day 5

Continuation Treatment (lasts 120 weeks for girls and 146 weeks for boys)

Treatment will depend on risk classification: low versus standard versus high risk

Treatment weeks 1 to 20:

Week Standard/High Risk Low Risk

1. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR

2. 6MP + ASP 6MP + MTX

3. 6MP + ASP 6MP + MTX

4. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR

5. 6MP + ASP 6MP + MTX

6. 6MP + ASP 6MP + MTX

7. Reinduction I§ Reinduction I

8. Reinduction I Reinduction I

9. Reinduction I Reinduction I

10. 6MP + ASP 6MP + MTX

11. DOX + VCR + 6MP + ASP 6MP + MTX

12. 6MP + ASP 6MP + MTX

13. 6MP + ASP 6MP + MTX

14. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR

15. 6MP + ASP 6MP + MTX

16. 6MP + ASP 6MP + MTX

17. Reinduction II Reinduction II

18. Reinduction II Reinduction II

19. Reinduction II Reinduction II

20. No chemotherapy 6MP + MTX

Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5 days, Days 1–5 Doxorubicin 30 mg/m2 IV, Day 1 Vincristine 2.0 mg/m2 IV push (max. 2 mg), Day 1 Mercaptopurine 50 mg/m2 PO daily x 7 days (std/high risk), Days 1–7 75 mg/m2 PO daily x 7 days (low risk), Days 1–7 L-asparaginase 25,000 Unit/m2 IM, Day 1 Methotrexate 40 mg/m2 IV or IM, Day 1

Reinduction I and II

This phase of treatment will be started at weeks 7 and 17 after bone marrow examination confirms complete remission. Reinduction treatment will be given twice: weeks 7 to 9 and weeks 17 to 19 for all patients.

Reinduction I for Standard/High Risk ALL:

Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1–8, 15, 21, Vincristine 1.5 mg/m2/week IV (max 2 mg) Days 1, 8, 15, Doxorubicin 30 mg/m2 Days 1, 8, L-asparaginase 25,000 Unit/m2 IM Days 1, 8, 15, Intrathecal chemotherapy, dose age dependent Day 1.

Reinduction II for Standard/High Risk ALL:

Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1–8, 15–21, Vincristine 1.5 mg/m2/week IV (max 2 mg) Days 1, 8, 15, L-asparaginase 25,000 Unit/m2, weekly IM Days 1, 8, 17, Intrathecal chemotherapy, dose age dependent Day 1 High-dose cytarabine 2 gm/m2 IV q 12 Days 15, 16

Reinduction I and II for Low Risk ALL

Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1–8, 15–21 Vincristine 1.5 mg/m2/week IV (max 2 mg), Days 1, 8, 15 L-asparaginase 10,000 Unit/m2/thrice weekly IM Days 2, 4, 6, 8, 10, 12, 15, 17, 19 Doxorubicin 30 mg/m2/week IV Day 1 Intrathecal chemotherapy, dose age dependent on Day 1

Treatment Weeks 21 to end of therapy Week Standard/High Risk Low Risk

21. 6MP + MTX 6MP + MTX

22. 6MP + MTX 6MP + MTX

23. Cyclo + Ara-C 6MP + MTX

24. DEX + VCR 6MP + DEX + VCR

25. 6MP + MTX 6MP + MTX

26. 6MP + MTX 6MP + MTX

27. Cyclo + Ara-C 6MP + MTX

28. DEX + VCR 6MP + DEX + VCR

Mercaptopurine 75 mg/m2 PO, daily x 7 days, Days 1–7 Methotrexate 40 mg/m2 IV or IM, Day 1 Cyclophosphamide 300 mg/m2 IV, Day 1 Cytarabine 300 mg/m2 IV, Day 1 Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5, Day 1–5 Vincristine 2.0 mg/m2 IV push (max. 2 mg), Day 1

The same treatment (weeks 21–28) will be repeated for a total of 6 times (until week 68). After week 68, all patients will receive daily 6MP and weekly MTX with pulses of dexamethasone and vincristine every 4 weeks until week 100, after which only 6MP and methotrexate will be given. Intrathecal treatment will be given every 8 weeks only to patients at high risk of CNS relapse after week 48 and will be discontinued after week 96. Continuation therapy will be discontinued after 120 weeks in girls and after 146 weeks in boys

Patients who meet the criteria of high-risk ALL are candidates for allogeneic hematopoietic stem cell transplantation. However, if the option is declined by the patients or guardians, or the procedure is deemed unsuitable by the attending physician and the principal investigator, the patient will remain on study and continue to receive chemotherapy.

https://clinicaltrials.gov/ct2/show/record/NCT00137111

¥Modified parts have been writing in italic form. In remission induction; standard dose prednisone changed by pulse methylprednisolone.

Disclosure statement

No potential conflict of interest was reported by the authors.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.