Prophylactic and Preemptive Therapy with Dasatinib after ...

LETTER TO THE EDITOR

Prophylactic and Preemptive Therapy with Dasatinib after Hematopoietic Stem Cell Transplantation for Philadelphia ChromosomePositive Acute Lymphoblastic Leukemia To the Editor: Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1 ALL) respond poorly to conventional chemotherapy, with reported long-term overall survival (OS) rates of 10%. Recent induction therapy based on tyrosine kinase inhibitors (TKIs), alone or in combination, has achieved complete response rates as high as 75%-95%; however, these promising results are transitory, and effective long-term maintenance strategies are lacking [1-3]. Although one retrospective study has suggested that upfront therapy with imatinib might make it possible to avoid consolidation therapy with allogeneic hematopoietic stem cell transplantation (HSCT), the presence of the Ph chromosome remains a primary indication for HSCT. Indeed, patients treated with HSCT have a 30%-60% increase in long-term survival rates and a lower risk of relapse [4,5]. The presence of minimal residual disease (MRD) after allogeneic or autologous HSCT for Ph1ALL is highly predictive of hematologic relapse. Considerable research has been focused on investigating the impact of TKIs, given either prophylactically or after detection of bcr-abl transcripts, on the incidence of MRD, remission duration, and longterm treatment outcome in patients with Ph1ALL who underwent HSCT when in complete remission [6]. The effect of the first-generation TKI imatinib has been investigated in several studies, but the results are somewhat contradictory [7-10]. Kebriaei et al. [10] published the largest series of patients with Ph1ALL treated with a first-generation TKI before and after HSCT (31 cases), and found that neither pre-HSCT nor post-HSCT imatinib administration had a significant impact on transplantation outcome. In that study, only 1 patient was treated with dasatinib (70 mg/day) before and after HSCT. Overall, imatinib appears to have very limited efficacy in treating hematologic relapse of Ph1ALL, suggesting that second-generation 652

TKIs may be more suitable candidates for prophylactic or preemptive treatment after HSCT. To the best of our knowledge, no previous studies have investigated the efficacy of dasatinib for this purpose. The aim of this preliminary study was to investigate the efficacy, safety, and tolerability of post-HSCT dasatinib in eradicating Ph1ALL and preventing relapse. Between 2005 and 2011, 10 patients with Ph1ALL (4 females and 6 males; median age, 41 years; range, 18-56 years) underwent autologous (n 5 2) or allogeneic (n 5 8) HSCT in our center. The patients represented 70% of the total number of patients with Ph1ALL attending our center during that period. Written informed consent was obtained from all patients, and the treatment schedule was approved by the local Ethical Committee. The median follow-up was 17 months post-HSCT. Patient characteristics are summarized in Table 1. Both qualitative and quantitative PCR assays were used to detect and estimate the levels of bcr-abl transcripts. mRNA was extracted from peripheral blood using the EXTRAzol Kit, and synthesis of cDNA was performed with the RT-Kit Plus (both from Nanogen Advanced Diagnostics, Turin, Italy). Qualitative detection of the t(9:22) translocation (variants P190, P210, and P230) was done using the Philadelphia Oligomix Alert Kit, and detection and measurement of cDNA of bcr-abl transcripts was performed using the PHILADELPHIA P190 Q-PCR Alert AmpliMIX and PHILADELPHIA P210 Q-PCR Alert AmpliMIX Kits (all from Nanogen Advanced Diagnostics). The p190 (e1a2) and p210 (b2a2 or b3a2) bcr-abl transcripts were expressed in 80% and 20% of the patients, respectively. One-half of the patients had cytogenetic aberrations other than the classic t(9;22) translocation. Nine patients received induction therapy with TKIs: 4 with dasatinib 140 mg and 5 with imatinib 600 mg. One patient received induction therapy based on chemotherapy alone (daunorubicin, vincristine, and asparaginase). After induction, patients received consolidation with high-dose cytarabine and mitoxantrone (HAM) or modified hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, methotrexate, and cytarabine). Before HSCT, all patients achieved a complete hematologic and cytogenetic response. Four of the patients considered to be in complete cytogenetic remission still had detectable MRD. Two patients in first complete molecular remission underwent autologous HSCT after a conditioning regimen based on alkeran 200 mg/m2. The remaining 8 patients (4 in complete molecular remission)

8 21‡ Negative Positive; T315I mutation 100 mg from day + 50 — 50 mg from day +118 Pleural effusion (grade 2) Negative Positive -

-

12 Negative — 100 mg from day +49 Negative NA

Letter to the Editor

35 43

45

22

18 37

5 6

7

8

9 10

M p190 t(9,22) + aberrations M p190 t(9,22) Dasatinib 140 mg HAM F p210 t(9,22) Dasatinib 140 mg HAM

47

*This patient experienced cytogenetic relapse after the first HSCT. †After second HSCT. ‡Death.

Positive Allogeneic unrelated Negative Allogeneic haploidentical

NA

50 mg from day +270 Positive Mild Grade II skin Allogeneic related Positive

Daunorubicin; HAM vincristine; asparaginase Dasatinib 140 mg HAM

Negative Autologous

87

22 17‡

Hematologic (grade 2) Negative Hematologic (grade 2) Positive; E255K mutation Hematologic (grade 2) Negative 50 mg from day +115 50 mg from day +71 Negative Negative Negative Allogeneic haploidentical Positive Allogeneic unrelated Hyper-CVAD Hyper-CVAD

HAM Imatinib 600 mg

Imatinib 600 mg Imatinib 600 mg

21 Negative — 100 mg from day +66 Negative NA

60 35 29 Negative 100 mg from day +153 Diarrhea (grade 1) Negative Positive 100 mg from day +133 — Negative Negative† 50 mg from day +112 Hematologic (grade 2) Negative Mild

Grade II liver NA Negative Allogeneic related Positive Allogeneic unrelated Negative Double allogeneic unrelated* Negative Autologous Dasatinib 140 mg HAM Imatinib 600 mg HAM Imatinib 600 mg Hyper-CVAD

4

Cytogenetics

F p190 t(9,22) M p210 t(9,22) F p190 t(9,22) + aberrations F p190 t(9,22) + aberrations M p190 t(9,22) M p190 t(9,22) + aberrations M p190 t(9,22) + aberrations 39 56 53 1 2 3

Consolidation Pre-HSCT Regimen MRD Induction Regimen Bcr/ Patient Age Sex Abl

Table 1. Clinical Features and HSCT Outcomes in 10 Patients with Ph+ALL

HSCT

Acute Chronic Post-HSCT GVHD GVHD MRD

Dasatinib Maintenance

Toxicity (NCI-CTC)

Maintenance MRD

OS Since Diagnosis, Months

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underwent allogeneic HSCT after a fully myeloablative conditioning regimen consisting of total body irradiation plus cyclophosphamide (4 patients) or treosulphan, fludarabine, and thiotepa (4 patients). The graft source was an HLA-matched sibling donor in 2 patients, an HLA-matched unrelated donor in 4 patients, and an HLA-haploidentical donor in 2 patients. Full donor stem cell engraftment was documented in all patients. Short-term methotrexate and cyclosporin A therapy was provided for graft-versushost disease (GVHD) prophylaxis. One of the 8 patients who underwent allogenic HSCT received a second allograft from another unrelated donor based on cytogenetic evidence of relapse after the first HSCT. Two patients developed acute grade II GVHD followed by mild chronic GVHD. After HSCT, MRD was still detectable in 3 patients. Two of these patients were MRD-positive before HSCT, and 1 patient became MRD-positive after HSCT (Table 1). Therapy with dasatinib was started at a median time of 113.5 days after transplantation (range, 49-270 days). Drug doses ranged between 50 mg and 100 mg daily, according to tolerability and compliance. Patients with grade 1 or lower toxicity according to National Cancer Institute Common Toxicity Criteria, version 4.0 (NCI-CTC) were treated with 100 mg/ day. In patients with grade 2 NCI-CTC, the dose was temporarily reduced to 50 mg/day. In patients with grade 3 NCI-CTC, the drug should be withheld and subsequently reintroduced at 50 mg/day if the grade drops to 1 or lower. If these patients again present toxicity greater than grade 1, then treatment with dasatinib definitely should be stopped. Treatment also must be interrupted in patients presenting with grade 4 NCI-CTC. Four of our patients developed grade 2 hematologic toxicity (neutropenia and thrombocytopenia), and 2 patients developed grade 1-2 nonhematologic toxicity (diarrhea/pleural effusion). Monitoring of cyclosporin A serum levels did not reveal any apparent interactions with dasatinib. Two patients with the kinase domain mutations T315I and E255K (highly resistant and resistant to imatinib, dasatinib, nilotinib, and bosutinib, respectively) died of ALL progression at 16 and 18 months after HSCT (Table 1). During maintenance treatment with dasatinib, MRD was negative in all 8 surviving patients, including 2 patients testing positive after HSCT. All patients are still receiving maintenance therapy with dasatinib, with a median duration of 15 months (range, 3-75 months). Median OS since diagnosis is currently 22 months (range, 8-87 months). The presence of MRD both before and early after HSCT is indicative of a poor prognosis. Posttransplantation maintenance therapy with imatinib has not yielded the desired results, and alternative approaches are needed to prevent hematologic relapse. Dasatinib has a 325-fold greater potency than imatinib

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Letter to the Editor

against cells with unmutated bcr-abl and is effective against several bcr-abl mutations that confer resistance to imatinib [11]. This molecule is also capable of determining molecular remission in patients with Ph1ALL and in Europe has been approved as second-line therapy for patients who fail previous therapy [2,3]. In vitro studies have shown that dasatinib exerts a more potent inhibitory action on c-kit and PDGFR-ß (IC50 values of 5 and 28 nM, respectively, compared with imatinib with IC50 values of 100 and 30 nM, respectively). It is possible that these immunomodulating properties also may contribute to reducing the risk of GVHD [12]. Based on our research results, dasatinib appears to be highly effective in preventing molecular relapse and eradication of Ph1ALL after HSCT. In view of the lack of guidelines in the literature and the poor outcome of relapsed Ph1ALL, we intend to continue dasatinib treatment until patients achieve 5-year complete molecular remission after HSCT. Although the data presented here are very encouraging, larger randomized clinical trials are needed to investigate the long-term safety and efficacy of dasatinib, as well as its eventual role in promoting resistant kinase domain mutations. REFERENCES 1. Vignetti M, Fazi P, Cimino G, 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;109:3676-3678. 2. Ravandi F, O’Brien S, Thomas D, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph1) acute lymphoblastic leukemia. Blood. 2010;116:2070-2077. 3. Fo
a R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011;118:6521-6528. 4. Lee HJ, Thompson JE, Wang ES, et al. Philadelphia chromosome-positive acute lymphoblastic leukemia: current treatment and future perspectives. Cancer. 2011;117:1583-1594. 5. Lee KH, Lee JH, Choi SJ, et al. Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed

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Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia. 2005;19:1509-1516. Mathisen MS, O’Brien S, Thomas D, et al. Role of tyrosine kinase inhibitors in the management of Philadelphia chromosome-positive acute lymphoblastic leukemia. Curr Hematol Malig Rep. 2011;6:187-194. Anderlini P, Sheth S, Hicks K, et al. Re: imatinib mesylate administration in the first 100 days after stem cell transplantation. Biol Blood Marrow Transplant. 2004;10:883-884. Ribera JM, Oriol A, Gonzalez M, et al. Programa Espa~ nol de Tratamiento en Hematologıa; Grupo Espa~ nol de Trasplante Hemopoyetico. 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;95:87-95. Wassmann B, Pfeifer H, Stadler M, et al. Early molecular response to posttransplantation imatinib determines outcome in MRD1 Philadelphia-positive acute lymphoblastic leukemia (Ph1 ALL). Blood. 2005;106:458-463. Kebriaei P, Saliba R, Rondon G, et al. Long-term follow-up of allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: impact of tyrosine kinase inhibitors on treatment outcomes. Biol Blood Marrow Transplant. 2011; e-pub ahead of print August 23, 2011; doi: 10.1016/j.bbmt.2011.08.011. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65:4500-4505. Walz C, Sattler M. Novel targeted therapies to overcome imatinib mesylate resistance in chronic myeloid leukemia (CML). Critic Rev Oncol Hematol. 2006;57:145-164.

Giovanni Caocci Adriana Vacca Antonio Ledda Francesca Murgia Eugenia Piras Marianna Greco Marcella Arras Sandra Atzeni Roberto Littera Giorgio La Nasa Hematology Unit, Department of Internistic Medical Sciences, University of Cagliari, Italy

Biol Blood Marrow Transplant 18: 652-654 (2012) Ó 2012 American Society for Blood and Marrow Transplantation doi:10.1016/j.bbmt.2011.12.587