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Keywords:

  • central nervous system relapse;
  • acute lymphoblastic leukaemia;
  • allogeneic bone marrow transplantation;
  • extended intrathecal therapy

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Conditioning regimen and graft versus host disease (GvHD) prophylaxis
  5. Extended intrathecal (IT) therapy
  6. Results
  7. Adverse events
  8. Disease relapse and survival
  9. Discussion
  10. References

We performed allogeneic bone marrow transplantation (BMT) with an extended period of post-transplant intrathecal (IT) chemotherapy for five patients with acute lymphoblastic leukaemia and non-Hodgkin's lymphoma who had relapsed in the central nervous system either in the very early phase or more than twice. Post-transplant IT was scheduled for a total of 12 doses over 18 months. One patient was found to have subclinical leucoencephalopathy. Disease relapse occurred in one patient and the other patients remained in complete remission for 39–196 months post-BMT. The estimated event-free survival was 80 ± 17·9% (standard error).

Due to recent advances in chemotherapy, acute lymphoblastic leukaemia (ALL) in childhood can now be successfully treated. However, about 20% of patients suffer from disease relapse, which occurs in the testicles and central nervous system (CNS) in about 2–3% of these cases (Pui et al, 1998; Schrappe et al, 2000). Patients with a first extramedullary relapse can be rescued by subsequent chemoradiotherapy, especially when the relapse occurs while off therapy (Gaynon et al, 1998; Ritchy et al, 1999). However, the disease can occasionally recur despite intensive salvage chemoradiotherapy and most patients who develop early CNS relapse during front-line chemotherapy cannot be rescued by chemoradiotherapy.

Allogeneic bone marrow transplantation (BMT) has been the treatment of choice for haematological relapse in patients with ALL (Barrett et al, 1994; Wheeler et al, 1998). However, it has been reported that the prognosis of children with a second isolated CNS relapse of ALL was very poor, even when the patients underwent BMT (Morris et al, 2003). Therefore, a novel treatment strategy is needed for patients with a second isolated CNS relapse of ALL.

Conditioning regimen and graft versus host disease (GvHD) prophylaxis

  1. Top of page
  2. Summary
  3. Methods
  4. Conditioning regimen and graft versus host disease (GvHD) prophylaxis
  5. Extended intrathecal (IT) therapy
  6. Results
  7. Adverse events
  8. Disease relapse and survival
  9. Discussion
  10. References

The conditioning regimen was based on total body irradiation in four patients. One patient received a busulphan-based regimen because the disease relapsed 1 month after cranial irradiation in the CNS. Prophylaxis for GvHD was ciclosporin  A (CSA) in cases of matched siblings or short-term methotrexate (MTX) with CSA or tacrolimus in mismatched cases.

Extended intrathecal (IT) therapy

  1. Top of page
  2. Summary
  3. Methods
  4. Conditioning regimen and graft versus host disease (GvHD) prophylaxis
  5. Extended intrathecal (IT) therapy
  6. Results
  7. Adverse events
  8. Disease relapse and survival
  9. Discussion
  10. References

Extended IT chemotherapy post-transplant was scheduled with cytarabine (Ara-C, 30 mg/m2) and hydrocortisone (HDC, 50 mg/m2) every 4 weeks after BMT for 3 months, and then every 8 weeks for another 15 months for a total of 12 doses. Magnetic resonance imaging (MRI) of the brain was performed at every IT therapy. When MRI revealed abnormal findings compatible with leucoencephalopathy (Padovan et al, 1998), regardless of the symptoms, further IT therapy was omitted.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Conditioning regimen and graft versus host disease (GvHD) prophylaxis
  5. Extended intrathecal (IT) therapy
  6. Results
  7. Adverse events
  8. Disease relapse and survival
  9. Discussion
  10. References

One patient (UPN 105) received craniospinal irradiation (CSI) during salvage chemotherapy, while the other patients did not because the duration of the second complete remission (CR) was too short to undergo scheduled CSI. A patient with Philadelphia chromosome-positive (Ph1) ALL (UPN 017) developed overt relapse 1 month after achieving the first CR, and BMT was performed 6 weeks later.

Adverse events

  1. Top of page
  2. Summary
  3. Methods
  4. Conditioning regimen and graft versus host disease (GvHD) prophylaxis
  5. Extended intrathecal (IT) therapy
  6. Results
  7. Adverse events
  8. Disease relapse and survival
  9. Discussion
  10. References

Veno-occlusive disease of the liver occurred in one patient (UPN 105). MRI showed leucoencephalopathy in one patient (UPN 079) without any symptoms at the sixth IT therapy, and further IT therapy was omitted. Four of the five patients developed acute GvHD. All three patients in grade III or IV were treated successfully with corticosteroids. Extensive chronic GvHD occurred in two patients (see Table I).

Table I.  Patient and donor characteristics and outcomes.
UPNAge (years)/sexDiagnosisDisease statusTime from diagnosis to BMT (months)Duration of second CR (months)DonorHLA disparityConditioningGvHD prophylaxisaGvHDcGvHDRelapseSurvival (months)Outcome
  1. ALL, acute lymphoblastic leukaemia; NHL, non-Hodgkin's lymphoma; LBL, lymphoblastic lymphoma; CR, complete remission; BMT, bone marrow transplantation; HLA, human leucocyte antigen; TBI, total body irradiation; CA, cytarabine; CY, cyclophosphamide; BUS, busulphan; l-PAM, l-phenylalanine mustard; GvHD, graft versus host disease; CSA, ciclosporin A; MTX, methotrexate; FK, tacrolimus; aGvHD, acute GvHD; cGvHD, chronic GvHD.

  2. HLAs were typed by serological tests only in the first three donor–recipient pairs and by DNA typing in the latter two.

0173/MPh1-ALL2nd CR41SiblingmatchedTBI/CA/CYCSAIVNoneNo196Alive
0793/FPrecursor-B ALL3rd CR204Sibling1 locus mismatchedTBI/CA/CYCSAINoneNo109Alive
1057/FPrecursor-B ALL4th CR497SiblingmatchedBUS/l-PAMCSA/MTX0NoneNo 92Alive
1779/MPrecursor-T ALL3rd CR354Mother1 locus mismatchedTBI/CA/l-PAMFK/MTXIIIExtensiveNo 39Alive
1784/FNHL (LBL)4th CR356Father2 loci mismatchedTBI/CA/CYFK/MTXIIIExtensiveYes (BM) 19Dead

Disease relapse and survival

  1. Top of page
  2. Summary
  3. Methods
  4. Conditioning regimen and graft versus host disease (GvHD) prophylaxis
  5. Extended intrathecal (IT) therapy
  6. Results
  7. Adverse events
  8. Disease relapse and survival
  9. Discussion
  10. References

The disease relapsed 12 months after BMT in the bone marrow of one patient (UPN 178). The other patients were disease free and well for 39–196 months. The estimated event-free survival was 80·0 ± 17·9% (SE).

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Conditioning regimen and graft versus host disease (GvHD) prophylaxis
  5. Extended intrathecal (IT) therapy
  6. Results
  7. Adverse events
  8. Disease relapse and survival
  9. Discussion
  10. References

Promising results have recently been reported with salvage chemoradiotherapy after the first CNS relapse in ALL (Ribeiro et al, 1995; Ritchy et al, 1999). However, the Medical Research Council reported that the prognosis of children after a second CNS relapse, including isolated and combined relapse, treated with conventional chemotherapy with or without BMT, was dismal (Morris et al, 2003). On the contrary, the Seattle group reported that the risk of post-transplant CNS relapse in patients with ALL who received post-transplant IT-MTX was lower than that in patients who did not receive such treatment (Thompson et al, 1986). In addition, they also reported that the risk of leucoencephalopathy was higher in patients who had received post-transplant IT-MTX.

Against this background, we started a novel treatment strategy for patients with ALL who experienced multiple CNS relapse and were thought to be incurable by salvage chemoradiotherapy (e.g. Ph1-ALL with CNS relapse): such patients should be treated with allogeneic BMT and post-transplant extended IT-Ara-C and -HDC.

It has been reported that IT-MTX could induce leucoencephalopathy, especially when combined with cranial irradiation (Filley & Kleinschmidt-DeMasters, 2001). Therefore, we did not use MTX as an IT therapeutic agent. Nevertheless, subclinical leucoencephalopathy occurred in one patient in our series. IT-MTX might not always be avoided, and serial MRIs should be performed to enable early diagnosis of leucoencephalopathy, which is an irreversible complication.

The optimal schedule of post-transplant IT therapy in patients with multiple CNS-relapsed ALL is unclear. We administered post-transplant IT chemotherapy 12 times over a period of about 18 months. Due to subclinical leucoencephalopathy, one patient (UPN 079) received only six applications of IT therapy and remained disease free. Therefore, our scheduled IT therapy might continue for too long or may involve too many treatment episodes in these cases. Although a randomized study would be desirable, such a study may be difficult, as there are very few patients with multiple CNS-relapsed ALL.

It has been reported that treatment failure after the first CNS relapse was due to toxicity, bone marrow relapse and extramedullary relapse, including a second CNS relapse (Ribeiro et al, 1995; Ritchy et al, 1999). Our encouraging results might be due to sufficient systemic treatment with the conditioning regimen, along with prolonged CNS treatment by post-transplant IT chemotherapy. Of course, it might be possible to treat patients with sufficient systemic therapy and autologous BMT if we could transplant non-contaminated grafts of leukaemic cells.

Recently, the stem cell source for BMT has become quite diverse. Matched- or mismatched-related and matched-unrelated bone marrow and -unrelated cord blood donors are available. Our patients underwent allogeneic BMT from matched- or mismatched-related donors. Although there was no transplant-related mortality (TRM) in our series, GvHD and other complications, including opportunistic infection, are relatively specific in allogeneic BMT. In addition, TRM is higher in mismatched-related and matched-unrelated transplant than in matched-related donors (Nagatoshi et al, 2004). However, we believe that the risks of TRM are acceptable for patients with multiple CNS relapse of lymphoid malignancies, as the prognosis of patients after a second CNS relapse is very poor.

In conclusion, allogeneic BMT combined with extended IT therapy appears to be an effective treatment option for patients with lymphoid malignancy with CNS relapse; serial cranial MRI examinations should be performed to avoid clinical leucoencephalopathy.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Conditioning regimen and graft versus host disease (GvHD) prophylaxis
  5. Extended intrathecal (IT) therapy
  6. Results
  7. Adverse events
  8. Disease relapse and survival
  9. Discussion
  10. References
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  • Filley, C.M. & Kleinschmidt-DeMasters, B.K. (2001) Toxic leukoencephalopathy. New England Journal of Medicine, 345, 425432.
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