Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Nilotinib restores long-term full-donor chimerism in Ph-positive acute lymphoblastic leukemia relapsed after allogeneic transplantation

Bone Marrow Transplantation volume 44, pages 263–264 (2009)Cite this article

The prognosis of adult patients with Ph chromosome-positive ALL (Ph+ ALL) is considered poor with an expected long-term survival of 20% at 10 years while no patients with less than a 3-log reduction in BCR-ABL transcripts were alive at 2 years.1 The combination of imatinib with chemotherapy in the induction therapy regimen had improved the response rate, but had not affected overall survival.2 Allo-SCT is still considered the treatment of choice in adults with this disease, despite the fact that post-SCT relapses are relatively frequent.3 A second allotransplant is rarely successful. Administration of imatinib early after SCT might be an effective approach to prevent recurrence of Ph+ ALL, but its feasibility has not been systematically evaluated.4 Second generation-targeted therapies, such as nilotinib (Novartis) and dasatinib (Bristol-Myers Squibb), have been evaluated for Ph+ ALL.5 Nilotinib monotherapy exhibits clinical activity in patients with relapsed/refractory Ph+ ALL with 26% achieving complete hematologic response (median treatment duration 1.8 months)6 while 31% achieved complete hematologic response with dasatinib (follow-up 6 months).7

A 36-year-old woman with Ph+ ALL, who was M-BCR- and m-BCR-positive and karyotype 46, XX, t(9;22) in 20/20 (100%) of metaphases analyzed without additional anomalies, received induction therapy according to the HyperCVAD regimen (hyperfractionated CY, VCR, doxorubicin and dexamethasone) in combination with imatinib mesylate 400 mg twice daily (BID).2 The hematologic and clinical outcome is described in Table 1. The patient developed early meningeal leukemia with a high blast count (18 × 109/l) that was treated by intrathecal MTX once a week for 6 weeks. After 3 weeks, she achieved complete hematologic response with persistence of M-BCR transcript at a value of 2.5% on quantitative PCR analysis;8 this percentage was actually a BCR-ABL/ABL ratio, calibrated on K562 cell line and not normalized to the international scale. On 30 June 2006, she received a sibling donor unmanipulated BM stem cell transplant after 12 Gy TBI in six fractions plus CY given by 1 h infusion of 60mg/kg/die × 2 days; acute GVHD prophylaxis consisted of CYA and MTX. Complete hemopoietic recovery was observed on Day +18 after transplant. No evidence of acute GVHD or infection was observed during the early transplant period. On Day +100, the patient was in complete response with a complete donor chimera confirmed by Gene Mapper Analysis (3130xl ABI Prism) on DNA extracted using a commercial kit. The BM M-BCR transcripts were positive at 0.025%. Leukemia relapse was documented 6 months later. At the time of relapse, the PCR was positive for M-BCR and m-BCR transcripts and karyotyping analysis showed additional anomalies. CYA was interrupted following relapse but no acute GVHD developed. She received no donor lymphocyte infusions. The patient was treated with idarubicin (15 mg per day on days 1 and 3) plus cytarabine (4500 mg/12 h for 3 days) but did not achieve any response. She was then treated with i.v. VCR 2 mg once a week for 2 weeks and dexamethasone 40 mg 4 days a week for 4 weeks. In addition, she received imatinib 400 mg BID over 28 days according to a modified regimen consisting of high-dose imatinib combined with VCR and dexamethasone.9 The patient achieved hematologic remission with persistence of M-BCR positivity and a mixed chimerism. Sequencing analysis of reverse transcriptase-PCR product found no BCR-ABL mutations. The patient was thus enrolled in a compassionate use protocol with nilotinib (Novartis). Nilotinib was initiated at standard dose 400 mg BID; after 6 months there was a dose reduction to 200 mg BID because of recurrent episodes of acute bronchitis and gastritis. The patient was treated with fluconazole and ciprofloxacin for Candida albicans and Pseudomonas aeruginosa infections detected by bronchoscopy and sputum culture. There was no interruption of nilotinib therapy. BM and chimerism were assessed on days 15 and 28 of the first cycle, and on day 28 of every even-numbered cycle. The patient was evaluated for cytogenetics at baseline and in repeated analyses. Safety assessments included an evaluation of adverse events, hematologic and cardiac enzyme assessments, biochemical testing, urinalysis, electrocardiography and physical examination. The treatment was well tolerated. She obtained a complete molecular remission, defined as PCR negativity of both M-BCR and m-BCR (confirmed by nested PCR), and her BM showed a complete chimera of the donor. At present, she is still in complete response with a full-donor chimerism 28 months after relapse and remains on nilotinib therapy at a dose of 200 mg BID.

Table 1 Clinical and hematologic outcome according to therapy
Full size table

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Kantarjian HM, O’Brien S, Smith TL, Cortes J, Giles FJ, Beran M et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000; 18: 547–561.

    Article  CAS  PubMed  Google Scholar 

  2. Wassmann B, Pfeifer H, Goekbuget N, Beelen DW, Beck J, Steljies S 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: 1469–1477.

    Article  CAS  PubMed  Google Scholar 

  3. Jabbour E, Cortes J, Kantarjian H, Giralt S, Jones D, Jones R et al. Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation related imatinib failure. Blood 2006; 108: 1421–1423.

    Article  CAS  PubMed  Google Scholar 

  4. Carpenter PA, Snyder DS, Flowers ME, Sanders JE, Gooley TA, Martin PJ et al. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood 2007; 7: 2791–2793.

    Google Scholar 

  5. Thomas DA . Philadelphia chromosome positive acute lymphocytic leukemia: a new era of challenges. Hematology Am Soc Hematol Educ Program 2007; 2007: 435–443.

    Article  Google Scholar 

  6. Ottmann OG, Larson RA, Kantarjian HM, Le Coutre P, Baccarani M, Haque A et al. Nilotinib in Patients (pts) with Relapsed/Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Who Are Resistant or Intolerant to Imatinib. Blood 2007; 110: (Abstract 2815).

  7. Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 2007; 7: 2309–2315.

    Article  Google Scholar 

  8. Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N et al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukaemia. A Europe Against Cancer program. Leukemia 2003; 12: 2318–2357.

    Article  Google Scholar 

  9. Réa D, Legros L, Raffoux E, Thomas X, Turlure P, Maury S et al. High-dose imatinib mesylate combined with vincristine and dexamethasone (DIV regimen) as induction therapy in patients with resistant Philadelphia-positive acute lymphoblastic leukemia and lymphoid blast crisis of chronic myeloid leukemia. Leukemia 2006; 20: 400–403.

    Article  PubMed  Google Scholar 

  10. Kaur P, Feldhahn N, Zhang B, Trageser D, Muschen M, Pertz V et al. Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia. Mol Cancer 2007; 6: 67–78.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Anne Freckleton for her help in preparing the paper.

Author information

Authors and Affiliations

  1. Institute of Hematology, Fondazione Policlinico San Matteo IRCCS, University of Pavia, Pavia, Italy

    S Merante, A A Colombo, S Calatroni, B Rocca, M Boni, P Bernasconi & E P Alessandrino

  2. Institute of Hematology and Medical Oncology ‘L. e A. Seragnoli’, Bologna, Italy

    S Soverini

  3. BU Oncology Novartis Farma S.p.A, Origgio, Italy

    L Bonvini

Authors
  1. S Merante
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A A Colombo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Calatroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B Rocca
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Boni
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P Bernasconi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Bonvini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Soverini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E P Alessandrino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Merante.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Merante, S., Colombo, A., Calatroni, S. et al. Nilotinib restores long-term full-donor chimerism in Ph-positive acute lymphoblastic leukemia relapsed after allogeneic transplantation. Bone Marrow Transplant 44, 263–264 (2009). https://doi.org/10.1038/bmt.2009.6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2009.6

This article is cited by

Search

Advanced search

Quick links