guidelines for the management of relapsed acute lymphoblastic

Guidelines for the management of relapsed acute lymphoblastic leukemia in childhood

Apollo Medicine 2011 DecemberReview Article

Volume 8, Number 4; pp. 297–301

© 2011, Indraprastha Medical Corporation Ltd

Guidelines for the management of relapsed acute lymphoblastic leukemia in childhood

Amita Mahajan**Senior Consultant, Paediatric Hematology and Oncology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi – 110076, India.

ABSTRACT

Considerable progress has been made in the treatment of newly diagnosed childhood acute lymphoblastic leuke-mia. With the use of intensive, risk-stratified multiagent chemotherapeutic protocols, over 80% of patients can hope to be long-term survivors. However, despite optimal treatment, about 20% of patients relapse. The treatment of these children poses a major challenge. The prognosis of these patients depends on a number of factors including time since diagnosis, the site of relapse and immunophenotype. The choice of postinduction therapy depends on these prognostic factors. Considerable work has been done to identify the subgroups of relapsed patients whose outcomes are significantly altered by allogeneic bone marrow transplant. In our scenario, the limited availability of allogeneic bone marrow transplant due to a host of factors renders the management of these children even more challenging.

Keywords: Acute lymphoblastic leukemia, relapse bone marrow transplant

Correspondence: Dr. Amita Mahajan, E-mail: [email protected]: 10.1016/S0976-0016(11)60011-2

Considerable advances have been made in the treatment of childhood acute lymphoblastic leukemia (ALL) over the past few decades with long-term cure rates approaching 85% in optimally treated children. However, despite optimal therapy, about 15–20% children will sustain a relapse. The treatment of children with relapsed ALL continues to be challenging.

In the 1980s, relapsed ALL was regarded an incurable disease. However, with sustained efforts and current sal-vage protocols, about 70–85% can hope to achieve a second remission, but only about 40% of these can hope to achieve a long-term cure. The optimal approach after achieving remission depends on a number of prognostic factors.

The prognosis for a child with ALL whose disease recurs depends on the time from diagnosis, the site of relapse, and immunophenotype.1,2 Patients with precursor B-cell ALL who experience either an isolated marrow relapse while on treatment or within 6 months of comple-tion of therapy or a combined relapse within 18 months of diagnosis have a very poor prognosis. Patients with an extramedullary relapse while on treatment or within 6 months of completion of therapy, patients with precursor B-cell ALL and a marrow relapse with or without an extramedullary relapse > 6 months after completing therapy, and patients with precursor B-cell ALL and a combined

marrow relapse between 18 and 36 months from the diag-nosis have an intermediate prognosis. Patients with a late extramedullary relapse (occurring more than 6 months after completing therapy) have a good prognosis. Patients with T-cell ALL who experience a bone marrow relapse with or without a concurrent extramedullary relapse at any point during treatment or posttreatment have a very poor prognosis.3,4

Despite these findings, no evidence exists that the early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) improves the outcome.5

The German Berlin–Frankfurt–Munster (BFM) group has developed risk stratification for relapsed ALL.6 In this risk stratification, the duration of the first complete remis-sion and the immunophenotype are associated with the outcome (Tables 1 and 2).

MANAGEMENT OF RELAPSED CHILDHOOD

ACUTE LYMPHOBLASTIC LEUKEMIA

The selection of therapy for the child whose disease recurs on or shortly after therapy depends on many factors including

09-AMJ-RA-AM.indd 297 12/8/2011 5:02:22 PM

298 Apollo Medicine 2011 December; Vol. 8, No. 4 Mahajan


prior treatment, whether the recurrence is medullary or extramedullary, and individual patient considerations.

The core principle in the management of relapsed ALL is to achieve a second remission followed by either (i) continuing chemotherapy or (ii) allogeneic hematopoietic stem cell transplantation.

REINDUCTION CHEMOTHERAPY

A lot of work has been done to design the optimal salvage protocols. These protocols need to combine drugs that are likely to be effective in previously treated patients and at the same time limit treatment-related morbidity and mortality in these patients which is significantly higher than the treat-ment naive group.

There are many salvage protocols. The two most com-monly used are from the UK-ALL group6 and the BFM group.7 All salvage protocols essentially aim at achieving a second remission using drugs identical to those used in the initial induction phase: Dexamethasone, epirubicin, vincris-tine and L-asparaginase.

Other drug combinations used for inducing remission for refractory relapsed ALL are the FLAG (fludarabine and cytarabine)8 and FLAG-Ida (fludarabine, idarubicin, and cytarabine). Newer agents such as clofarabine have gener-ally been tried in subsequent or posttransplant relapses.9 Relapsed T-cell ALL is notoriously difficult. Treatment of children with relapsed T-cell ALL with the T-cell selective agent nelarabine has demonstrated an approximately 50% response rate.10

The UK-ALL induction block comprises dexamethasone, epirubicin, vincristine and L-asparaginase followed by a consolidation block with systemic methotrexate, etoposide, cytarabine, vincristine, dexamethasone, epirubicin, cyclo-phosphamide, and 6-thioguanine.7 This is then followed by continuation blocks again using 6-MP and methotrexate and the pulses of prednisolone and vincristine but also cytarabine, etoposide, and cyclophosphamide.

The conceptual backbone of BFM relapsed ALL proto-cols6 is a series of short, intensive multiagent chemotherapy courses including the most known drugs with anti-leukemic efficacy with a 2-week interval between blocks to allow adequate marrow recovery. The BFM protocol comprises alternating blocks of chemotherapy after a cytoreductive phase followed by conventional maintenance therapy with daily 6-TG and biweekly methotrexate. The alternating blocks R1 (prednisolone, 6-MP, vincristine, vindesine, methotrexate, cytarabine, teniposide, and L-asparaginase) and R2 (dexamethasone, vindesine, methotrexate, ifosfa-mide, and daunorubicin). All patients receive intrathecal chemotherapy. The block therapy concept is feasible, effec-tive, and relatively well tolerated. Thus, it is incorporated into many other treatment protocols for relapsed ALL.11,12

TREATMENT AFTER REMISSION

A number of trials have looked at hematopoietic stem cell transplantation (HSCT) versus continuing chemotherapy for these patients.13–16 The choice of further therapy is deter-mined by the predicted risk of subsequent relapse as well as

Table 1 The German Berlin–Frankfurt–Munster relapse risk group assignment for precursor B-cell acute lymphoblastic leukemia.

Extramedullary relapse Combined bone marrow Marrow relapse and extramedullary relapse

Very early relapse (< 18 months from diagnosis) Intermediate High HighEarly relapse (> 18 months from diagnosis and Intermediate Intermediate High < 6 months from completion of therapy)Late relapse (> 6 months from completion of therapy) Standard Intermediate Intermediate

Table 2 The German Berlin–Frankfurt–Munster relapse risk group assignment for T-cell acute lymphoblastic leukemia.

Extramedullary relapse Combined bone marrow Marrow relapse and extramedullary relapse

Very early relapse (< 18 months from diagnosis) Intermediate High HighEarly relapse (> 18 months from diagnosis and Intermediate High High < 6 months from completion of therapy)Late relapse (> 6 months from completion of therapy) Standard High High

09-AMJ-RA-AM.indd 298 12/8/2011 5:02:23 PM

Guidelines for the management of relapsed ALL in childhood Review Article 299


the quantum of benefit expected from HSCT which is asso-ciated with significantly higher morbidity and mortality. In countries like ours, this is further determined by the feasi-bility of offering HSCT in view of the lack of a donor regis-try, limitations of access and the funding for HSCT.

There is adequate evidence now to suggest that mini-mal residual disease status after the induction of second remission is of prognostic significance and may further define the choice of postinduction therapy.17,18

The suggested treatment strategy is outlined based on their risk as determined by the BFM criteria.

LOW-RISK RELAPSED ACUTE

LYMPHOBLASTIC LEUKEMIA

For patients with a late marrow relapse, a primary chemo-therapy approach should be considered with HSCT reserved for a subsequent marrow relapse.18 Whether transplantation benefits patients with late marrow relapse but with a high level of residual disease after reinduction treatment is cur-rently under evaluation.

INTERMEDIATE-RISK RELAPSED ACUTE


For these patients, the benefit of HSCT versus continuing chemotherapy remains unclear as some of the advantages are offset by the increased treatment-related mortality for children who undergo HSCT. A Children’s Cancer Group trial (CCG-1941) comparing chemotherapy versus HSCT (either matched sibling or matched unrelated donor) was not able to show a significant advantage for HSCT over chemotherapy for patients relapsing <12 months after stop-ping therapy.16

HIGH-RISK RELAPSED ACUTE


Hematopoietic stem cell transplantation should be strongly considered for patients with T-cell ALL and marrow relapse; or patients with precursor B-cell ALL and marrow relapse occurring while on treatment or within 6 months of termi-nation of therapy; or late marrow relapse with high tumor load as indicated by a peripheral blast count of 10,000/μL or more. For such patients, allogeneic transplant from an

HLA-identical sibling or matched unrelated donor which is performed in the second remission has been reported to result in longer leukemia-free survival when compared with a chemotherapy approach.

Despite transplant, however, the outcome of this sub-group is very poor especially if relapsing on therapy.

MATCHED UNRELATED TRANSPLANTATION

The outcome following matched unrelated donor trans-plants has improved significantly over the past decade and may offer an outcome similar to that obtained with the matched sibling donor transplants.19,20 Treatment-related mortality remains high (> 20%), and the rates of clinically extensive chronic graft-versus-host disease remain high. However, there is some evidence that the matched unre-lated donor transplantation may yield a lower relapse rate.21 There is also evidence that transplant conditioning regimens that include total-body irradiation produce higher cure rates than chemotherapy-only preparative regimens.22

A Center for International Blood and Marrow Trans-plant Research study suggests that the outcome after one or two antigen mismatched cord blood transplant may be equivalent to that for a matched family donor or for a matched unrelated donor.23 In certain cases, where no suit-able donor is found or an immediate transplant is considered crucial, a haploidentical transplant utilizing large doses of stem cells may be considered. For all types of transplants, pre-transplant level of minimal residual disease (MRD) is an important prognostic factor; patients with high levels of pre-transplant MRD have a very poor prognosis.24

SECOND RELAPSE

For patients relapsing after an allogeneic HSCT for relapsed ALL, a second ablative allogeneic HSCT may be feasible. However, many patients will be unable to undergo a second HSCT procedure due to failure to achieve remission, early toxic death or severe organ toxicity related to salvage chemotherapy. Among the highly selected group of patients who are able to undergo a second ablative allogeneic HSCT, about 10–30% may achieve long-term event-free survival (EFS). Prognosis is more favorable for patients with longer duration of remission after the first HSCT and for patients with complete remission at the time of the second HSCT.

09-AMJ-RA-AM.indd 299 12/8/2011 5:02:23 PM

300 Apollo Medicine 2011 December; Vol. 8, No. 4 Mahajan


ISOLATED CENTRAL NERVOUS SYSTEM

RELAPSE

With the improved success of treatment of children with ALL, the incidence of isolated extramedullary relapse has decreased. The incidence of isolated central nervous system (CNS) relapse is < 10% and testicular relapse is < 5%. While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy followed by craniospinal radiation has improved the outlook particularly for patients who did not receive cranial radiation during their first remission.25 In a Paediatric Oncology Group (POG) study using this strategy, children who had not previously received radiation therapy and whose initial remission was 18 months or greater had a 4-year EFS rate of about 80% compared with EFS rates of about 45% for children with CNS relapse within 18 months of diagnosis.26 In a follow-up study, chil-dren who had not previously received radiation therapy and with initial remission of 18 months or more were treated with intensive systemic and intrathecal chemotherapy for 1 year followed by 18 Gy of cranial radiation only. The 4-year EFS was 78%. Children with an initial remission of < 18 months also received the same chemotherapy but had craniospinal radiation (24 Gy cranial/15 Gy spinal) as in the first POG study. This group’s 4-year EFS was 52%.

A number of case series describing stem cell transplan-tation in the treatment of isolated CNS relapse have been published. This approach may be of value in patients with high risk of relapse using chemoradiation treatment. In a study comparing the outcome of patients treated with either HLA-matched sibling transplants or chemoradiother-apy as in the POG studies above, however, 8-year prob-abilities of leukemia-free survival adjusted for age and duration of first remission were similar (58% and 66%, respectively).27

ISOLATED TESTICULAR RELAPSE

The standard approach for treating isolated testicular relapse is to administer chemotherapy plus radiation ther-apy. While there is limited clinical data concerning the out-come without the use of radiation therapy, this treatment strategy is being tested in clinical trials. The results of the treatment of isolated testicular relapse depend on the timing of the relapse. The 3-year EFS of boys with overt testicular relapse during therapy is about 40%; it is about 85% for boys with late testicular relapse.

TREATMENT OPTIONS UNDER CLINICAL

EVALUATION

A novel nucleoside analog clofarabine has been tried in children with relapsed ALL as well as acute myeloid leuke-mia (AML) and appears promising.28 It is well tolerated and shows significant antileukemic activity in heavily pre-treated children including those relapsing post-bone mar-row transplantation.

A number of clinical trials are currently underway to investigate novel treatment approaches.29,30 These include the evaluation of new formulations of existing chemothera-peutic agents, new anti-metabolites and nucleoside analogs, monoclonal antibodies against leukemia-associated anti-gens and molecular therapies that target the genetic abnor-malities of the leukemia cells and their affected signaling pathways.

REFERENCES

1. Gaynon PS, Qu RP, Chappell RJ, et al. Survival after relapse in childhood acute lymphoblastic leukemia: impact of site and time to first relapse—the Children’s Cancer Group Experience. Cancer 1998;82:1387–95.

2. Chessells JM, Veys P, Kempski H, et al. Long-term follow-up of relapsed childhood acute lymphoblastic leukaemia. Br J Haematol 2003;123:396–405.

3. Uderzo C, Conter V, Dini G, et al. Treatment of childhood acute lymphoblastic leukemia after the first relapse: curative strategies. Haematologica 2001;86:1–7.

4. Rivera GK, Zhou Y, Hancock ML, et al. Bone marrow recur-rence after initial intensive treatment for childhood acute lymphoblastic leukemia. Cancer 2005;103:368–76.

5. Rubnitz JE, Hijiya N, Zhou Y, et al. Lack of benefit of early detection of relapse after completion of therapy for acute lymphoblastic leukemia. Pediatr Blood Cancer 2005;44:138–41.

6. Roy A, Cargill A, Love S, et al. Outcome after first relapse in childhood acute lymphoblastic leukaemia—lessons from the United Kingdom R2 trial. Br J Haematol 2005;130:67–75.

7. Einsiedel HG, von Stackelberg A, Hartmann R, et al. Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin–Frankfurt–Münster Group 87. J Clin Oncol 2005;23:7942–50.

8. Sarper N, Yalman N. FLAG (fludarabine, high-dose cytarab-ine and G-CSF) for refractory and high-risk relapsed acute leukemia in children. Med Pediatr Oncol 2000;34:163.

09-AMJ-RA-AM.indd 300 12/8/2011 5:02:23 PM

Guidelines for the management of relapsed ALL in childhood Review Article 301


9. Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol 2006;24:1917–23.

10. Berg SL, Blaney SM, Devidas M, et al. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children’s Oncology Group. J Clin Oncol 2005;23:3376–82.

11. Buchanan GR, Rivera GK, Pollock BH, et al. Alternating drug pairs with or without periodic reinduction in children with acute lymphoblastic leukemia in second bone marrow remission: a Pediatric Oncology Group Study. Cancer 2000;88:1166–74.

12. Rivera GK, Hudson MM, Liu Q, et al. Effectiveness of inten-sified rotational combination chemotherapy for late hemato-logic relapse of childhood acute lymphoblastic leukemia. Blood 1996;88:831–7.

13. Wheeler K, Richards S, Bailey C, et al. Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UK-ALL X experi-ence. Medical Research Council Working Party on Childhood Leukaemia. Br J Haematol 1998;101:94–103.

14. Borgmann A, von Stackelberg A, Hartmann R, et al. Unre-lated donor stem cell transplantation compared with chemo-therapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis. Blood 2003;101:3835–9.

15. Hahn T, Wall D, Camitta B, et al. The role of cytotoxic ther-apy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 2005;11:823–61.

16. Eapen M, Raetz E, Zhang MJ, et al. Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children’s Oncology Group and the Center for International Blood and Marrow Transplant Research. Blood 2006;107:4961–7.

17. Eckert C, Biondi A, Seeger K, et al. Prognostic value of mini-mal residual disease in relapsed childhood acute lymphoblas-tic leukaemia. Lancet 2001;358:239–41.

18. Coustan-Smith E, Gajjar A, Hijiya N, et al. Clinical signifi-cance of minimal residual disease in childhood acute lym-phoblastic leukemia after first relapse. Leukemia 2004;18:499–504.

19. Bunin N, Carston M, Wall D, et al. Unrelated marrow trans-plantation for children with acute lymphoblastic leukemia in second remission. Blood 2002;99:3151–7.

20. Saarinen-Pihkala UM, Gustafsson G, Ringdén O, et al. No disadvantage in outcome of using matched unrelated donors as compared with matched sibling donors for bone marrow transplantation in children with acute lymphoblastic leukemia in second remission. J Clin Oncol 2001;19:3406–14.

21. Gassas A, Sung L, Saunders EF, et al. Graft-versus-leukemia effect in hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia: significantly lower relapse rate in unrelated transplantations. Bone Marrow Transplant 2007;40:951–5.

22. Bunin N, Aplenc R, Kamani N, et al. Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood and Marrow Transplant Consortium study. Bone Marrow Transplant 2003;32:543–8.

23. Eapen M, Rubinstein P, Zhang MJ, et al. Outcomes of trans-plantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 2007;369:1947–54.

24. Sramkova L, Muzikova K, Fronkova E, et al. Detectable min-imal residual disease before allogeneic hematopoietic stem cell transplantation predicts extremely poor prognosis in chil-dren with acute lymphoblastic leukemia. Pediatr Blood Cancer 2007;481:93–100.

25. Ritchey AK, Pollock BH, Lauer SJ, et al. Improved survival of children with isolated CNS relapse of acute lymphoblastic leukemia: a pediatric oncology group study. J Clin Oncol 1999;17:3745–52.

26. Barredo JC, Devidas M, Lauer SJ, et al. Isolated CNS relapse of acute lymphoblastic leukemia treated with intensive sys-temic chemotherapy and delayed CNS radiation: a pediatric oncology group study. J Clin Oncol 2006;24:3142–9.

27. Eapen M, Zhang MJ, Raetz E, et al. Outcomes after HLA-matched sibling transplants or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse. Blood 2006;107: 4961–7.

28. Kurtzberg J, Ernst TJ, Keating MJ, et al. Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol 2005;23:3396–403.

29. Pui CH, Jeha S. New therapeutic strategies for the treatment of acute lymphoblastic leukaemia. Nat Rev Drug Discov 2007;6:149–65.

30. Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol 2006;24:1917–23.

09-AMJ-RA-AM.indd 301 12/8/2011 5:02:23 PM

Apollo hospitals: http://www.apollohospitals.com/Twitter: https://twitter.com/HospitalsApolloYoutube: http://www.youtube.com/apollohospitalsindiaFacebook: http://www.facebook.com/TheApolloHospitalsSlideshare: http://www.slideshare.net/Apollo_HospitalsLinkedin: http://www.linkedin.com/company/apollo-hospitalsBlog:Blog: http://www.letstalkhealth.in/

guidelines for the management of relapsed acute lymphoblastic

Health & Medicine