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Keywords:

  • chronic myeloid leukemia;
  • new tyrosine kinase inhibitors;
  • imatinib;
  • transplantation;
  • failure;
  • toxicity

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) are increasingly likely to have received a novel tyrosine kinase inhibitor (NTKI) after failing imatinib mesylate. It is unknown whether the use of these NTKIs before HSCT increases transplant-related toxicity.

METHODS.

The outcome of 12 patients with CML (1 in chronic phase, 6 in the accelerated phase, and 5 in the blastic phase) who received dasatinib (n = 2), nilotinib (n = 7), or both (n = 3) before HSCT were retrospectively analyzed.

RESULTS.

The median time on treatment was 134 days, and the median time from the end of NTKI therapy to HSCT was 34 days. The preparative regimen was ablative in 8 patients and nonablative in 4. All patients engrafted within 13 days. There was no significant early transplant-related toxicity. One patient developed secondary graft failure after 6 months from the first HSCT that required a second HSCT. Acute and chronic graft-versus-host disease (GVHD) was observed in 7 and 6 patients, respectively. Nine patients achieved a molecular response: 4 complete and 5 major (quantitative reverse transcriptase-polymerase chain reaction <0.05%). Three patients had disease progression by Day 30 after HSCT. Two patients developed disease recurrence after a median of 12 months. After a median follow-up of 10 months, 7 patients were alive in molecular response and 5 patients had died, 4 of disease progression and 1 of extensive chronic GVHD.

CONCLUSIONS.

Previous treatment with NTKI did not increase transplant-related toxicity in this preliminary experience. Further follow-up and a larger number of patients will be necessary to confirm these observations. Cancer 2007. © 2007 American Cancer Society.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for selected patients with BCR-ABL-positive chronic myeloid leukemia (CML).1 This form of treatment, however, can be associated with high rates of treatment-related mortality and morbidity. Imatinib mesylate, a tyrosine kinase inhibitor, has produced remarkable results, including complete cytogenetic responses (CCyR) in up to 90% of patients and major molecular responses (MMR) in 40% to 60%, leading to a >30% decrease in the number of HSCT performed over the last 3 years.2–5 Resistance to imatinib, however, is an increasingly recognized problem, and mutations of the kinase domain are the most frequently defined mechanism of resistance.6–8

Novel, more potent tyrosine kinase inhibitors are undergoing clinical trials with promising results. Nilotinib (AMN-107) is 10 to 30 times more potent than imatinib, and is capable of inhibiting the kinase activity of most BCR-ABL kinase domain mutants reported to be associated with imatinib failure.9, 10 In a phase I trial, a cytogenetic response was achieved by 41% of patients in chronic (CP) or accelerated phase (AP) treated with nilotinib, and in 14% of patients in blast phase (BP).11 Dasatinib (BMS-354825), a dual Src- and Abl-kinase inhibitor, is 100–300-fold more potent than imatinib.10, 12 Phase I studies of this drug documented cytogenetic response rates of 59%, 40%, and 56% in patients in CP, AP, and BP, respectively.13 These novel tyrosine kinase inhibitors (NTKIs) have been well tolerated. Both drugs can produce myelosuppression. Dasatinib-induced pleural effusions have been reported in a small percentage of patients, whereas nilotinib may be associated with transient elevation of bilirubin, mostly indirect.11, 13

Patients failing imatinib may be effectively treated with HSCT, and prior treatment with imatinib does not increase the rates of transplant-related toxicity.14, 15 In view of the reported efficacy and good toxicity profile associated with nilotinib and dasatinib, patients will be increasingly likely to receive second-line treatment with 1 of these drugs before being referred for transplantation. However, to our knowledge, the effect of prior exposure to these agents on outcomes of HSCT is unknown. In the current study, we analyzed the short-term transplant-related toxicity among patients who received nilotinib or dasatinib before HSCT.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients and Conditioning

Between December 2004 and May 2006, 12 consecutive patients treated with nilotinib or dasatinib for imatinib-resistant CML received HSCT from human leukocyte antigen (HLA)-matched related donors (n = 7), unrelated donors (n = 3), a haplo-identical donor (n = 1), and unrelated cord blood (n = 1). Preparative regimens were intravenous busulfan-based in 8 cases and fludarabine and melphalan in 4 cases (Table 1). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate at a dose of 5 mg/m2 given intravenously on Days 1, 3, 6, and 11 after transplantation. All patients received granulocyte-colony-stimulating factor at a dose of 5 μg/kg daily from Day 7 until neutrophil engraftment. Informed consent was obtained in all cases. This study was approved by the Institutional Review Board.

Table 1. Patient and Treatment Characteristics
UPNAge, ySexStageTyrosine kinase inhibitorDays on treatmentBest response before HSCTMutation before HSCTStage at HSCTDays to HSCT*Donor typePreparative regimenStem cell source
  • UPN indicates unique patient number; y, year; HSCT, hematopoietic stem cell transplantation; M, male; AP, accelerated phase; NR, no response; BP, blast phase; MUD, matched unrelated donor; BuCy, intravenous busulfan at a dose of 0.8 mg/kg every 6 hours for 16 doses and cyclophosphamide at a dose of 60 mg/kg for 2 days; BM, bone marrow; F, female; NR, no response; CP, chronic phase; CCyR, complete cytogenetic response; FluBu, fludarabine at a dose of 40 mg/m2 for 4 days, intravenous busulfan at a dose of 130 mg/ m2 for 2 days and antithymocyte globulin; MRD, matched related donor; FluMel, fludarabine at a dose of 30 mg/m2 for 4 days and melphalan at a dose of 140 mg/m2; PB, peripheral blood; Minor CyR, minor cytogenetic response; CHR, complete hematologic response; PHR, partial hematologic response; Haplo, haploidentical donor.

  • *

    Days from interruption of novel tyrosine kinase treatment to HSCT.

140MAPDasatinib45NRT315IBP50MUDBuCyBM
225FCPDasatinib90CCyRNoCCyR10MUDFluBuBM
351FBPNilotinib110NRQ252HCP67MRDFluMelPB
455MBPNilotinib60Minor CyRNoBP21MRDBuCyPB
556MBPNilotinib45CHRNoCP15MRDFluMelPB
659MAPNilotinib30NRNoCP130MRDFluMelPB
729MAPNilotinib150CHRQ252HCHR27MRDFluBuPB
846MAPNilotinib1502nd CPE255KBP40MRDFluBuPB
947MAPNilotinib114NRY253HAP40MUDBuCyBM
1027MBPNilotinib/dasatinib180PHRNoBP7HaploFluMelThiotepaPB
1118MBPNilotinib/dasatinib244CCyRE255VCCyR10Cord bloodFluBuCord
1239FAPNilotinib/dasatinib285CCyRA433TCP60MRDFluBuPB

Response Assessment

Standard criteria were used to score CML response.16 BCR-ABL transcripts were detected by real-time quantitative reverse-transcriptase polymerase chain reaction (Q-PCR) analysis on peripheral blood and/or bone marrow aspirate and negative results were confirmed by nested PCR, as reported previously.17 A complete molecular response (CMR) was defined as undetectable BCR-ABL transcript levels. An MMR was defined as BCR-ABL:ABL ratios <0.05%. All patients were tested for BCR-ABL kinase domain mutations by DNA sequencing. Mutations were confirmed by sequencing of forward and reverse strands.8 Hematopoietic chimerism was evaluated on peripheral blood or bone marrow cells by analysis of DNA microsatellite polymorphisms by PCR with D6S264, D3S1282, D18S62, and D3S1300 fluorescence-labeled primers, then analyzed using GeneScan software in all cases. Mixed chimerism was defined as the presence of any detectable (≥1%) recipient DNA.

Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (version 2.0). GVHD was graded according to standard criteria.18

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics

Twelve patients (1 in CP, 6 in AP, and 5 in BP) were assessed. The median age was 41 years (range, 18–59 years). Two patients (1 in CP and 1 in AP) received dasatinib (at doses of 50 mg twice daily and 70 mg twice daily, respectively), 7 patients (4 AP cases and 3 BP cases) received nilotinib (800 mg/day [n = 3] and 400 mg twice daily [n = 4]), and 3 patients (1 in AP and 2 in BP) received both nilotinib (400 mg twice daily) and dasatinib (70 mg twice daily) for a median of 134 days (range, 30–285 days). Four patients (1 receiving dasatinib and 3 receiving nilotinib) did not respond and received salvage therapy: 3 patients received a combination of idarubicin and cytarabine (1 patient received 2 cycles and 2 patients received 1 cycle) and 1 patient received a combination of hydroxyurea and anagrelide for 15 days. The remaining responded to NTKI therapy. Best responses were a CCyR in 3 patients, a minor cytogenetic response (Minor CyR) in 1 patient, complete hematologic responses in 2 patients (CHR), a partial hematologic response (PHR) in 1 patient, and a return to second CP in 1 patient. Five patients lost their response (CCyR, Minor CyR, CHR, PHR, and second CP, respectively). The median time from the end of therapy to HSCT was 34 days (range, 7–130 days). At the time of HSCT, 4 patients were in BP, 1 was in AP, 4 were in second CP, 1 was in CHR, and 2 were in CCyR (Table 1). Before HSCT, 5 different kinase domain mutations were detected in 7 patients (Q252H [2 patients], Y253H [1 patient], E255K/V [2 patients], T315I [1 patient], and A433T [1 patient]).

Engraftment, Toxicity, and GVHD

All patients were engrafted. The median time to neutrophil and platelet engraftment was 13 days (range, 11–30 days) and 19 days (range, 14–35 days), respectively. There were no major toxicities: nausea and vomiting (grade ≤3) were observed in 5 patients, diarrhea (grade 1) in 4 patients, mucositis (grade 2) in 4 patients, and increased liver function tests in (grade 1) in 1 patient. None of the patients developed venoocclusive disease of the liver. Treatable bacterial infections occurred in 4 patients, viral infections (cytomegalovirus) in 2 patients, and fungal infections (aspergillosis) in 1 patient. Acute grade 2 skin GVHD was observed in 6 patients; grade 2 ocular and hepatic GVHD in 2 patients each, respectively; and grade 2 gastrointestinal tract GVHD in 1 patient. Six patients developed chronic GVHD involving the skin (n = 4 patients), eyes (n = 2 patients), liver (n = 2 patients), and gastrointestinal tract (n = 1 patient).

Outcome

Chimerism studies at Day 30 and Day 100 after HSCT were 100% of donor type in 8 patients (67%) and 9 patients (75%), respectively. Nine patients achieved a molecular response. Four patients achieved a CMR, and remained free of disease progression after a median of 14+ months (range, 8–20+ months). One of these patients who had received an unrelated donor transplant developed secondary graft failure of unknown etiology 5 months after HSCT. He received fludarabine, melphalan, and ATG followed by a second HSCT from the same donor; he engrafted and was in molecular disease remission at the time of last follow-up, at 12 months and 7 months, respectively, after the first and second HSCT. Five patients achieved an MMR; 2 subsequently developed disease recurrence: the first patient developed disease recurrence at 6 months after HSCT and died 5 months later (he harbored a T315I mutation before and after HSCT) and the second patient developed disease recurrence at 18 months after HSCT and was receiving salvage therapy at the time of last follow-up. The 3 other patients remained disease-free at 4 months after HSCT. Three patients had progressive disease at 1 month after HSCT; all had kinase domain mutations: Q252H and E255K/V. Two patients died of disease progression at 5 months and 2 months, respectively, after HSCT and the third went back into a short-lived molecular remission after nilotinib treatment and the development of acute GVHD; he died 6 months later. Overall, 5 patients had died at the time of last follow-up (4 from disease progression [they harbored T315I, Q252H, E255K, and E255V kinase domain mutations] and 1 from chronic GVHD [Q252H]) after a median of 6 months (range, 2–11 months) from HSCT. Transplant outcomes are summarized in Table 2.

Table 2. Transplant Outcomes
UPN no.Days to ANC >500/mm3Days to platelet >20,000/mm3Donor chimerism on transplant day +30Donor chimerism on transplant day +100Day +100 BCR-ABL/ABLToxicity (Grade)InfectionsAcute GVHD (Grade)Chronic GVHDBest responseCytogenetic recurrenceDFS, moStatusSurvival, mo
  1. UPN indicates unique patient number; ANC, absolute neutrophil count; GVHD, graft-versus-host disease; DFS, disease-free survival; N, nausea; V, vomiting; D, diarrhea; CMV, cytomegalovirus antigenemia; MMR, major molecular response; CMR, complete molecular response; GI, gastrointestinal; M, mucositis; LFT, increased liver functional tests; PD, progressive disease; NA, not applicable.

11214100%100%0.046NV(1)Bacterial pneumoniaOcular (1)LiverMMRYes6Dead11
D(1)CMV
21317100%100%0.09NoneNoneNoneNoneCMRNo12+Alive (secondary engraftment failure)12+
31422100%100%0NoneE. coliSkin(2)Skin/GICMRNo8Died in CMR (c GVHD, sepsis)8
CMV
41135100%100%0NV(1)NoneSkin(2)OcularMMRYes18Alive22+
M(2)
D(1)
51720100%100%0.01NoneAspergillusNoneSkinCMRNo20+Alive20+
61415100%100%0D(1)NoneNoneSkinCMRNo15+Alive15+
71219MixedMixed0.21NV(1)NoneSkin(2)SkinPDNA1Dead6
LFT(1)Liver(2)Liver
Ocular(2)Ocular
813NAMixedMixedNAM(2)EnterococcusSkin (2)NAPDNA1Dead3
D(2)PneumoniaLiver (1)
91217100%100%0NV(2)NoneSkin (2)NoneMMRNo5+Alive5+
101117100%100%19Cystitis(1)NoneNoneNoneMMRNo3+Alive3+
1130NAMixedNANAM(2)Bacterial pneumoniaNoneNAPDNA2Dead2
121216Mixed100%0.04M(2)NoneSkin (2)NoneMMRNo3+Alive3+
NV(3)GI (2)

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

To our knowledge, this is the first report on the feasibility of HSCT after previous dasatinib or nilotinib therapy. Specifically, we demonstrated that the previous treatment with the NTKIs did not interfere with speed of engraftment and achievement of full donor chimerism. Most important, in our series of patients we did not observe excessive organ toxicity, including nilotinib-specific or dasatinib-specific side effects.11, 13 There were no regimen-related deaths.

In the current series, despite the unfavorable composition of the group under study, with resistant and advanced stage disease, nonrecurrence mortality was low (1 patient, or 8%). This is comparable to rates reported in the context of imatinib use before HSCT.14, 15 Engraftment failure is a feared complication of allogeneic transplantation, and it is unclear whether any of the TKIs can increase the risk of that complication. In the current series, 1 patient treated with dasatinib developed secondary graft failure, responsive to a second HSCT from the same donor. Others have reported that with the use of imatinib before HSCT the incidence of engraftment failure is in the range of 10%. All series, however, investigated small numbers of patients and the potential impact of these drugs on engraftment is unknown.

A high rate of molecular responses was achieved after HSCT, despite the fact that all patients underwent transplantation while they harbored imatinib-refractory advanced disease stages. Dasatinib and nilotinib may have the potential advantage of rescuing patients failing imatinib therapy, allowing transplantation with a smaller disease bulk, which should improve disease control after HSCT.

In summary, treatment with NTKIs did not appear to increase transplant-related toxicity in this small series of patients. Larger number of patients treated with these and other TKIs will be needed to confirm our observations.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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