The results of the retrospective multicentre study of the therapy of Ph-positive acute lymphoblastic leukemia according to the protocols of the Russian research group

Introduction. Since 2009, the RALL Group has been treating Ph-positive ALL by protocols based on a continuous chemotherapeutic approach with TKI combination. Based on the results of the studies received in 2011, a protocol was developed for ALL-2012 for the treatment of Ph-positive ALL, in which chemotherapy was de-escalated.

Aim. The aim of the study was to compare the efficacy and long-term results in patients treated by  ALL-2009 protocol with TKI and ALL-2012 protocol.

Materials and methods. The study included patients with newly diagnosed Ph-positive ALL who received therapy from 2009 to 2017 in one of 3 centers: 12 patients who were treated according to the ALL-2009 protocol with TKI, and 23 patients treated according to the ALL-2012 protocol. The study does not include patients who have been treated in other centers.

Results. Two deaths were recorded on each protocol: ALL-2009 with imatinib – 1 (8%) in induction and  1 (8%) in consolidation; ALL-2012 – 1 (4%) patient in induction and 1 (4%) in consolidation treatment. There were no significant differences in the frequency of complete remissions after induction courses, and their incidence was 83% and 87%, respectively. In group of patients that were treated by ALL-2009 protocol with ITK, the frequency of complete molecular remission after 2 courses of induction therapy (the 70th day of the protocol) was 43% (3 of 7 patients), and those who received therapy by ALL-2012 protocol – 55% (in 11 of 20 patients).

The differences in the frequency were not statistically significant (p > 0.05).

Refractory of the disease was detected in 1 (8%) of the patients on the ALL-2009 protocol with ITK and in  1 (4%) of the patients on the ALL-2012 protocol. In all patients with Ph-positive ALL (n = 35) the overall survival was 55% and the disease-free survival was 40%. Fourteen (40%) of 35 patients underwent transplantation of hematopoietic stem cells.

The conclusion. According to the retrospective multicentre study of the RALL, it was shown that  de-intensification of chemotherapeutic treatment against the background of constant therapy of TKI did  not affect the effectiveness of therapy.

1. Pullarkat V., Slovak M.L., Kopecky K.J., Forman S.J., Appelbaum F.R. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008; 111(5): 2563–72.

2. Burmeister T., Schwartz S., Bartram C.R., Gokbuget N., Hoelzer D., Thiel E.; GMALL study group. Patients age and BCR-ABL frequency in adult B-precursor ALL: a retrospective analysis from the GMALL study group. Blood. 2008; 112(3): 918–9.

3. Chiaretti S., Vitale A., Cazzaniga G., Orlando S.M., Silvestri D., Fazi P., et al. Clinico-biological features of 5202 patients with acute lymphoblastic leukemia enrolled in the Italian AIEOP and GIMEMA protocols and stratified in age cohorts. Haematologica. 2013; 98(11): 1702–10.

4. Swerdlow S.H., Campo E., Harris N.L., Jaffe E.S., Pileri S.A., Stein H., et al. World Health Organization classification of tumors of haematopoietic and lymphoid tissues. lyon: IARC; 2008.

5. Larson R.A., Dodge R.K., Burns C.P., Lee E.J., Stone R.M., Schulman P., et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia. Cancer and Leukemia Group Study 8811. Blood. 1995; 85(8): 2025–37.

6. Laport G.G., Alvarnas J.C., Palmer J.M., Snyder D.S., Slovak M.L., Cherry A.M., et al. Long-term remission of Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors: a 20-year experience with the fractionated total body irradiation-etoposide regimen. Blood. 2008; 112(3): 903–9.

7. Hoelzer D., Thiel E., Loffler H., Buchner T., Ganser A., Heil G., et al. Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood. 1988; 71(1): 123–31.

8. Gokbuget N., Hoelzer D. Treatment of Adult Acute Lymphoblastic Leukemia. ASH Educational Pr. Book Hematology, 2008; 133–41. Available at: http:// asheducationbook.hematologylibrary.org/content/2006/1/133.long (accessed 14 Dec 2017)

9. Fielding A.K., Rowe J.M., Richards S.M., Buck G., Moorman A.V., Durrant I.J., et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: Results from the international ALL trial MRC UKALLXII/ ECOG2993. Blood. 2009; 113(19): 4489–96.

10. Thomas D.A., Faderl S., Cortes J., O’Brien S., Giles F.J., Kornblau S.M., et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004; 103(12): 4396–407.

11. Thomas D.A., Kantarjian H.M., Cortes J., Ravandi F., Faderl S., Jones D., et al. Outcome after frontline therapy with the hyper-CVAD and imatinib mesylate regimen for adults with de novo or minimally treated Philadelphia Chromosome (Ph) positive acute lymphoblastic leukemia (ALL). Blood. 2008; 112(11): Abstr. 2931. Available at: http://www.bloodjournal.org/content/112/11/2931?sso-checked=true (accessed 14 Dec 2017)

12. Yanada M., Takeuchi J., Sugiura I., Akiyama H., Usui N., Yagasaki F., et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J. Clin. Oncol. 2006; 24(3): 460–6.

13. Towatary M., Yanada M., Usui N., Takeuchi J., Sigiura I., Takeuchi M., et al. Combination of intensive chemo- therapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia. Blood. 2004; 104(12): 3507–12.

14. Lee K.H., Lee J.H., Choi S.J., Lee J.H., Seol M., Lee Y.S., et al. Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia. 2005; 19(9): 1509–16.

15. Lee K.H., Kim Y.J., Min C.K., Kim H.J., Eom K.S., Kim D.W., et al. The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosomepositive acute lymphoblastic leukemia. Blood. 2005; 105(9): 3449–57.

16. Wassmann B., Pfeifer H., Goekbuget N., Beelen D.W., Beck J., Stelljes M., et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2006; 108(5): 1469–77.

17. de Labarthe A., Rousselot P., Huguet-Rigal F., Delabesse E., Witz F., Maury S., et al. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood. 2007; 109(4): 1408–13.

18. Delannoy A., Delabesse E., Lheritier V., Castaigne S., Rigal-Huguet F., Raffoux E., et al. Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphiapositive acute lymphoblastic leukemia: results of the GRAALL AFR09 study. Leukemia. 2006; 20(9): 1526–32.

19. Vignetti M., Fazi P., Cimino G., Martinelli G., Di Raimondo F., Ferrara F., et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood. 2007; 109(9): 3676–8.

20. Chiaretti S., Vitale A., Vignetti M., Piciocchi A., Fazi P., Elia L., et al. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016; 101(12): 1544–52.

21. Foa R., Vitale A., Vignetti M., Meloni G., Guarini A., De Propris M.S., et al; GIMEMA Acute Leukemia Working Party. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011; 118(25): 6521–8.

22. Chalandon Y., Thomas X., Hayette S., Cayuela J.M., Abbal C., Huguet F., et al; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015; 125(24): 3711–9.

23. Moorman A.V., Harrison C.J., Buck G.A., Richards S.M., Secker-Walker L.M., Martineau M., et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/ Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007; 109(8): 3189–97.

24. Daver N., Thomas D., Ravandi F., Cortes J., Garris R., Jabbour E., et al. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica. 2015; 100(5): 653–61.

25. Parovichnikova E.N. Results of the treatment of Ph-positive acute adult lymphoblastic leukemia by the protocol of the State Scientific Center of the Russian Academy of Medical Sciences. Clinical Oncohematology. Basic Research and Clinical Practice. Russian journal (Klinicheskaya onkogematologiya). 2010; 3(1): 75. (in Russian)

26. Davidyan Yu.R., Parovnikikova E.N., Troitskaya V.V., Sokolov A.N., Klyasova G.A., Kuzmina L.A., etc. Therapy of Ph-positive acute lymphoblastic leukemia. Results of the research group RALL. Clinical oncohematology. Basic Research and Clinical Practice. Russian journal (Klinicheskaya onkogematologiya). 2011; 4(4): 315–9. (in Russian)

27. Ribera J.M., Oriol A., Gonzalez M., Vidriales B., Brunet S., Esteve J., et al. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica. 2010; 95(1): 87–95.

28. Lee S.H., Kim Y.J., Chung N.G., Lim J., Lee D.G., Kim H.J., et al. The extent of minimal residual disease reduction after the first 4-week imatinib therapy determines outcome of allogeneic stem cell transplantation in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2009; 115(3): 561–70.

29. Gokbuget N., Hoelzer D. Treatment of adult acute lymphoblastic leukemia. Semin. Hematol. 2009; 46(1): 64–75.