Line Tyrosine Kinase Inhibitors Research Articles

Prognostic Factors in Treatment of Chronic Myeloid Leukemia with Tyrosine Kinase Inhibitors- Single Center Experience.

Abstract 2210Poster Board II-187 Background:Imatinib mesylate (IM), a targeted inhibitor of the BCR-ABL tyrosine kinase, is widely used to treat chronic myeloid leukemia (CML). However, considerable number of patients fails to achieve or loose complete cytogenetic response (CCyR) or major molecular response (MMR). The mechanisms of failure in the majority of cases are unknown. Identification of patients who may subsequently fail to respond to imatinib would provide a considerable aid to clinical management. Few long-term retrospective population-based data on the outcome of these patients are available. Aims:To identify prognostic factors that can predict failure of treatment with tyrosine kinase inhibitors (TKI), and to optimise CML therapy after first line TKI failure. Patients and methods:The retrospective population-based analysis included 138 patients (68 females, 70 males, median age 47 yrs) in early chronic phase (ECP) (n=63), late chronic phase (LCP) (n=60) or accelerated phase (AP) (n=15) of CML. All enrolled patients were treated with IM 400mg/day for CP or 600 mg/day for AP as a first line TKI. Patients were monitored for cytogenetic and molecular response every 6 and 3 months respectively using conventional cytogenetic on bone marrow and quantitative PCR (RQ-PCR) on peripheral blood. Results of RQ-PCR were expressed as a ratio of BCR-ABL/ABL% [IS]. Definitions of CCyR, MMR as well as CP and AP were consistent with European LeukemiaNet recommendations. The analyzed factors included: time to complete hematologic remission (CHR), time to CCyR, time to MMR and additional cytogenetic abnormalities in Ph positive cells [ACA Ph(+)] during first line IM treatment and % of CCyR and MMR during second line TKI treatment. To estimate probability of CCyR and MMR cumulative incidence analysis was used. Cytogenetic and molecular progression free survival (PFS) was estimated by Kaplan-Meier analysis. Results:Probability of CCyR for the analyzed group was 55%, 60% and 62% after 12, 18 and 24 months of treatment with IM respectively. Probability of cytogenetic PFS was 92%, 83%, 81% and 76% in 12, 18, 24 and 36 months respectively. There was observed statistically significant correlation between probability of achievement of CCyR, MMR and the following: time to CHR, time to imatinib introduction, phase of the disease and ACA Ph(+). No correlation between probability of CCyR, MMR and age, sex, Sokal and Hasford risk factors was observed. 1) Early CHR in up to 8 weeks after diagnosis (dx) predicted CCyR and MMR achievement irrespective of treatment schedule to CHR (p<0,0001) (Fig 1.). [Display omitted] 2) Early IM introduction up to 4 months since dx increased probability of CCyR and MMR in 12 and 18 months respectively (p<0,0001). 3) Patients in LCP were significantly less likely to obtain CCyR and MMR comparing to ECP and results in this group were similar to AP patients (p=0,0004) (Fig. 2). [Display omitted] 4) Early CCyR up to 6 months after starting IM increased probability of MMR (p<0,0001). 5) ACA Ph(+) were confirmed as an adverse prognostic factor regarding to achieving (p=0,005) and maintaining (p=0,01) of CCyR. 6) Treatment with higher dose of IM predicted better outcome when ACA Ph(+) at diagnosis and/or at least 10% of blasts in bone marrow or peripheral blood at dx were considered as AP criteria. 7) Among patients after IM failure those treated with 2G TKI were more likely to achieve and maintain CCyR (52%) than those with escalation of IM (24%) (p=0,02). Conclusions:These data suggest need of 1) therapy intensification from the very moment of diagnosis, 2) early achievement of CHR, 3) early IM introduction (<4 months from dx in analysed population), 4) the precise defining of AP with rigid criteria may result in better outcome. 5) Relative risk (Sokal and Hasford) relationship with treatment results seems to be not sufficient when IM is introduced after a long time since diagnosis. 5) Treatment switch to 2G TKI but not imatinib escalation after first line IM treatment failure is proposed to be an optimal treatment standard. Disclosures:Foryciarz:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Sacha:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Florek:BMS: Research Funding; Novartis: Research Funding. Czekalska:BMS: Research Funding; Novartis: Research Funding. Zawada:Novartis: Research Funding; BMS: Research Funding. Skotnicki:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Comparison of Healthcare Utilization and Costs Between Nilotinib and Dasatinib as Second Line Therapies in Chronic Myeloid Leukemia.

Abstract 4286 IntroductionDasatinib and nilotinib are both indicated to treat chronic myeloid leukemia (CML) patients resistant or intolerant to imatinib. This study compared retrospectively the healthcare resource utilization and costs associated with dasatinib versus nilotinib treatment as second line therapies in CML patients. Patients and MethodsTwo large administrative claims databases were combined (MarketScan and Ingenix Impact, 01/2002-12/2008) to identify patients diagnosed with CML (ICD-9 code 205.1x) and treated with a tyrosine kinase inhibitor (TKI) second line therapy. Patients with at least 1 prescription of dasatinib or nilotinib and no prior use of TKI other than imatinib were selected to form the dasatinib second line therapy group and nilotinib second line therapy group, respectively. The index date was defined as the first prescription for dasatinib or nilotinib. Only patients with an index date on or after the date of nilotinib FDA approval (10/27/2007) and continuously enrolled at least 1 month prior to and 1 month after the index date were included. Patients were followed for up to 6 months from the index date to the earliest of the termination of healthcare plan enrollment, or end of data availability. Patient total medical visits, as well as outpatient visits and hospitalization days, were compared between the two groups using incidence rate ratios (IRR). Multivariate negative binomial regression models were applied to estimate IRR while adjusting for baseline differences of the two groups. Patient total costs, pharmacy costs, and medical service costs (including costs associated with outpatient visits, inpatient admissions, emergency room visits, and other medical services) were compared between the nilotinib and dasatinib group. Unadjusted and adjusted cost differences were estimated for each cost component using generalized linear models (GLM) or two-part models. Multivariate regression models to compare patient utilization and costs controlled for potential differences in age, gender, and cancer complexity (Darkow 2007) between the two groups. Costs were adjusted for inflation to 2008 U.S. dollars. ResultsA total of 230 CML patients treated with a second line TKI met the selection criteria; 186 patients treated with dasatinib and 44 patients treated with nilotinib were identified. Average age was similar between the two groups: 56.9 ± 16.3 in dasatinib patients and 54.1 ± 12.4 in nilotinib patients (p=.366) and the ratio of females was not statistically different: 44.1% v 56.8% (p=.128). Comorbidity burden, measured by the Charlson comorbidity index, was also similar between the two groups: 3.12 ± 1.90 for dasatinib patients vs. 3.07 ± 1.95 for nilotinib patients (p=.638), as was the proportion of patients with moderate and severe CML complexity: 53.8% vs 61.4% (p=.362) and 27.4% vs 22.7% (p=.526) for dasatinib and nilotinib treated patients, respectively. Mean duration of prior imatinib treatment for both groups was not statistically significant (p=0.189), 662.1 days vs 583.8 days, for nilotinib Vs dasatinib, respectively. Over the follow-up period, dasatinib patients had significantly more medical visits (IRR=1.32, p=.028), as well as outpatient visits (IRR=1.31, p=.033). Dasatinib patients also had 36% more hospital days but the difference was not statistically significant (IRR=1.36, p=0.664). Over the 6 months following the initiation of the second line therapy, compared to patients on nilotinib, patients on dasatinib incurred $18,328 (p<.001) more in total medical services and $6,367 (p=0.04) less in pharmacy costs, resulting in a higher net total healthcare cost of $12,039 (p=.035). The difference in medical costs was mainly explained by the difference of inpatient costs ($12,480 higher for dasatinib patients; p=<.001) and outpatient costs ($5,035 higher for dasatinib patients; p=.001). ConclusionThis preliminary analysis of total cost of treatment data showed that among CML patients treated with a second line TKIs, those treated with dasatinib were associated with higher total healthcare costs and more frequent health care resource utilization than patients treated with nilotinib. Results may be updated when more data on nilotinib patients becomes available. Disclosures:Wu:Novartis: Consultancy, I am working for Analysis Group Inc and Analysis Group Inc received funds from Novartis to conduct the analysis. Bollu:Novartis Oncology: Employment. Guo:Novartis Pharmaceuticals Corporation: Employment. Guerin:Novartis: Consultancy, I am working for Analysis Group Inc and Analysis Group Inc received funds from Novartis to conduct the analysis. Tsaneva:Novartis: Consultancy, I am working for Analysis Group Inc and Analysis Group Inc received funds from Novartis to conduct the analysis. Williams:Novartis Pharmaceutical Corporation: Employment. Griffin:Novartis Pharmaceutical Corporation: Consultancy, I have.

Current Leukemia Free Survival After Tyrosine Kinase Inhibitor (TKI) for Chronic Myeloid Leukemia (CML): A New Method That Accounts for Restoring Response with Sequential TKI.

Abstract 2197Poster Board II-174 Background:Imatinib is very effective for patients with CML in chronic phase (CP). While some patients (pts) may fail therapy with imatinib (because of resistance or intolerance), effective salvage therapy is available with new generation TKI (dasatinib, nilotinib, bosutinib). Currently the efficacy of each therapy is judged by their individual impact on overall survival (OS) and event free survival (EFS). However calculations of EFS for a patient does not take into account the effect of successful salvage therapy with subsequent TKI. We therefore studied the current leukemia free survival (CLFS) to obtain a more accurate impression of the outcome of pts with CML treated with sequential TKI. Aim:To provide an accurate estimation of long-term outcome with TKI therapy among pts with CML treated with sequential TKI. Methods:All pts with CP CML who received imatinib after failure to interferon-alpha (IFN) therapy at MD Anderson Cancer Center (MDACC) were included n this analysis. Events were defined as failure to achieve a complete cytogenetic response (CCyR) by 12 months of therapy, loss of CCyR, or discontinuation of therapy because of toxicity or any other causes after 18 months without achieving CCyR. Pts who failed imatinib either went to a 2nd TKI or other class of therapy. EFS is defined as survival without evidence of relapse at anytime after imatinib while CLFS is defined as survival without evidence of leukemia relapse at the time of most recent assessment. Thus, a loss of response would count as an event, but a response to salvage therapy would “repair” that event. Pts receiving any therapy other than a TKI after imatinib or other TKI is counted as an irreparable failure. Results:Three hundred and five pts were treated at MDACC with imatinib after IFN failure. The median age was 54 years (range 23-81), 169 (55%) were males. Median time on IFN was 1.5 yrs (range 0.1-10 yrs). Best response to IFN was MCyR in 114 (37%), minor cytogenetic response in 35 (11%), and CHR in 86 (28%). Among the others, 15 were intolerant to IFN, 29 pts were resistant and 26 pts had an unknown response. Reasons for being off IFN included 141 (46%) cytogenetics .{/MAIN;137}resistance, 37 (12%) hematological resistance, 123 (40%) intolerance, and 4 (1%) unknown. On imatinib 201 (66%) pts achieved CCyR; 64 of them discontinued imatinib in CCyR because of toxicity or other reasons, none of 64 pts received a 3rd line TKI. 27 (9%) pts who failed imatinib were treated with another TKI and attained CCyR. Of them, 18 remained in CCyR, 7 eventually lost CCyR, and 2 lost CCyR but attained and maintained CCyR with a 3rd TKI. Seventy-seven (25%) pts failed imatinib and could not be salvaged either due to unavailability of a 2nd TKI or failure to achieve CCyR with a 2nd TKI. EFS for this patient population is 63% at 7 years, whereas the CLFS is 70%. Conclusion:CLFS can measure the actual benefit of TKI therapy by accounting for failures and subsequent responses. Despite the unavailability of 2nd generation TKI during the early part of the observation period, the CLFS of 71% at 7 years demonstrates the extraordinary benefit obtained with these agents alone or, when needed, in sequence. [Display omitted] Disclosures:Kantarjian:BMS: Research Funding; Novartis: Research Funding. Cortes:Novartis: Research Funding; BMS: Research Funding.

Patterns of imatinib resistance mutation analysis in chronic myeloid leukemia (CML) patients on imatinib at the time of loss of response to the drug in Asian Indian subjects

7079 Background: The treatment of (CML) has undergone major changes in the past decade with the introduction of tyrosine kinase inhibitors (TKI). However the initial enthusiasm is waning with increasing recognition of drug resistance. There is an urgent need to identify the types of receptor mutations which lead to drug resistance and their significance in salvage therapy. Methods: We identified 17 males and 8 female patients with median age 40 yrs (range 9–55 years) with CML who were on imatinib at the time of loss of hematologic response (HR), cytogenetic (CyR), or molecular response (MR) and performed imatinib-resistance mutation analysis. The sequencing was done on ABI machine by direct sequencing method. Results: This group included 22 patients with chronic phase (CP) disease, 2 patients with accelerated phase (AP), and 1 patient with extramedullary blast crisis (BC). Fourteen patients received treatment with agents other than imatinib as the first-line therapy due to either nonavailability of the drug at the time of diagnosis in India, but were started on imatinib when drug became available. The other 11 patients received imatinib as first-line therapy. The best response to imatinib included major CyR in 14 patients which included 3 patients with complete CyR and minor CyR in 6 patients. Lack of HR was noted in 2 patients in whom CyR was not evaluated. Imatinib resistance mutation analysis was prompted by no HR (n = 2); loss of HR after achieving CyR (n = 9); failure to achieve CyR milestones (n = 3); loss of CyR (n = 9); development of extramedullary BC (n = 1). The analysis revealed no mutations-11 patients, M351T-4 patients, G250E-3 patients, F317L-2 patients, M244V- 1 patient, T315I-1 patient, F382L-1 patient, results awaited in 4 patients with 2 patients showing 2 mutations. Conclusions: The majority of patients 11/25 had no detectable mutations while T315I which confers resistance to all TKIs was detected only in 1/25 patients who demonstrated loss of response in our population. The correlation of the other mutations to loss of response and the response to second line TKI needs to be studied in further detail. In addition analysis of mutation patterns at baseline may help in stratifying patients for treatment. No significant financial relationships to disclose.

Survival advantage in patients treated with high-dose interleukin-2 (HDIL2) for metastatic renal cell carcinoma (mRCC)

e16039 Background: A prognostic index developed at MSKCC(Memorial-Sloan-Kettering Cancer Center) relates to survival in mRCC patients (pts) treated with interferon. We evaluated 79 pts treated first line with HDIL2 to see if this prognostic index is applicable. Eligibility for HDIL2 was based on cardiopulmonary screening and performance status (PS). Method: Medical records were analyzed retrospectively from 2000–2008. Pts were categorized into favorable, intermediate &amp; poor risk category according to MSKCC prognostic index, which includes time from diagnosis to treatment, serum calcium &amp; LDH, hemoglobin and PS. Median survival (OS) &amp; median progression free survival (PFS) were compared between risk categories. Results were evaluated taking into consideration potential confounders such as subsequent treatment with tyrosine kinase inhibitors (TKI) &amp; time from nephrectomy to metastasis interval of more than 1 year. Statistical analysis utilized SPSS. Results: 29 pts (36.7%) were treated with TKIs subsequently and this had no impact on median OS compared to those not receiving TKIs. 19 pts (24%) had nephrectomy to metastasis interval of more than 1 year and this also did not impact on OS analysis compared to those with shorter time to metastasis. Poor risk group was not analyzed due to small sample size. Conclusions: Median OS for mRCC pts eligible for and treated with HDIL2 as first line therapy exceeds reports of other first line treatment, either cytokines or TKIs. The survival advantage occurs regardless of being in either favorable or intermediate risk category and this benefit is not confounded by subsequent treatment with TKIs or nephrectomy to treatment interval more than 1 year. HDIL2 pts requires good PS and organ function, but 72% were intermediate risk pts. Thus, MSKCC risk categories do not predict for HDIL2 treatment outcome. HDIL2 should still be considered as a first line agent for mRCC, in the era of TKIs, as long as patients meet the eligibility criteria, as it infers survival advantage. [Table: see text] [Table: see text]

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in the Imatinib-Era: High Survival Rate Following Allogeneic HSCT after Imatinib Failure: Results of the German CML Study IV

Allogeneic HSCT remains an important option for patients with chronic myeloid leukemia (CML) who failed imatinib. Focus has been on second line tyrosine kinase inhibitors (TKI). Little is known on the outcome of HSCT for such patients. In July 2002, the German CML-Study Group activated a prospective randomized trial comparing different imatinib based strategies in chronic phase CML (CP). Elective early HSCT was considered for patients (pts) with EBMT score 0–1 for those with high disease risk, and after imatinib failure. By the end of July 2008, 1197 pts were randomized. In 80 (6,5 %) pts HSCT was documented. 52 pts were male (65%), 23 were high risk pts (28%) according to the Euro score. Median age at diagnosis was 37 years (yrs) (range 16–62), median time to HSCT was 12.6 months (mo, range 3.5–54 mo). EBMT score was 0–1 in 8 (10%), 2 in 10 (12%), 3–4 in 44 (55%) and 5 in 18 pts (23%). Median follow-up after HSCT was 19 mo (range 0–59). Cumulative response rates prior to HSCT were 68% for complete hematologic response, 23% for complete cytogenetic responses, and 9% for major molecular responses. Based on the indication for HSCT three groups were defined:early HSCT (n= 19, 23%; low EBMT score (n=9), high risk pts (n=7), patient request (n=3);HSCT after imatinib failure or intolerance in first CP (n=34, 43%) andHSCT in second CP or higher, accelerated phase or blast crisis (n=27, 34%).14 pts died, 10 deaths were transplantation related, 4 CML related. Two pts with a molecular relapse were successfully treated with donor lymphocyte infusion in combination with TKI. Overall survival rate at two yrs for group one was 87.8%, for group two 93.8%, and for group three 49.5%. By EBMT score, survival rates were 100% for risk score 0–2, 82.2% for risk score 3–4, and 43.5% for risk score 5. Data from this prospective controlled cohort study clearly show that HSCT remains an attractive and important rescue therapy for CML patients with imatinib failure or intolerance, particularly for those with a low EBMT risk score.HSCT in 1st CPearly HSCTHSCT for failure and intolerance in 1st CPTotalHSCT in advanced phasesN19345327Euro scorehigh68149intermediate312157low10142411% male63566078Median age (range)35 (16–56)38 (21–56)37 (16–56)37 (18–62)Median time to HSCT (Range) (months)8.5 (4.8–23.6)17,5 (5.0– 53.7)12.6 (4.8 53.7)12.0 (3.5–54.1)EBMT score0–15380254913–4926359>=501117Best responseCHR11/1828/3439/5214/26CCyR3/1710/3313/504/22MMR2/173/315/482/19Response at HSCTBC00024AP0003CP1934530HR1119300Ccyr2240MMR0000Transplant sourceSibling1010209Unrelated9243318Conditioning therapystandard14213517reduced3694other2796SourcePB13263922BM68145Dead22410TRM2246CML0004Probability of survival at 2 years after HSCT87.8%93.8%91.4%49.5%

FIP1L1-PDGFRα D842V, a Novel Panresistant Mutant, Emerges after Treatment of FIP1L1-PDGFRα T674I Eosinophilic Leukemia with Single Agent Sorafenib

Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative neoplasm characterized by the FIP1L1-PDGFRA fusion gene, variant PDGFRA fusions, or other genetic lesions. Most FIP1L1-PDGFRA positive patients enjoy durable complete molecular responses to low-dose imatinib, but resistance mediated by a T674I mutation in the ATP-binding pocket of PDGFRA has been reported in advanced disease. Sorafenib, a potent inhibitor of RAF-1, B-RAF, VEGFR and PDGFR, has been shown to be active against this mutant in vitro. We explored a case of FIP1L1-PDGFRα T674I CEL in blast crisis that was treated with sorafenib as single agent. A partial hematological response was induced, but three months later, progression to blast crisis again occurred. At this time point, sequencing of FIP1L1-PDGFRA revealed the presence of a novel FIP1L1-PDGFRα D842V mutant, while FIP1L1-PDGFRα T674I was no longer detected. The sensitivity of this mutant to different inhibitors was further explored using FIP1L1-PDGFRα D842V transformed Ba/F3 cells. The growth of FIP1L1-PDGFRα D842V transformed Ba/F3 cells was highly resistant to sorafenib and PKC412, in addition to imatinib and dasatinib (IC50 ≥ 1000 nM for imatinib, sorafenib and dasatinib; IC50 of PKC412 not reached due to toxicity above 500 nM). Consistent with these dose response curves, FIP1L1-PDGFRα D842V cells did not undergo apoptosis when cultured in 500 nM sorafenib, imatinib or dasatinib, while 30% of FIP1L1-PDGFRα cells did under the same conditions. Analysis of FIP1L1-PDGFRα autophosphorylation and phosphorylation of the downstream signaling proteins ERK1 and ERK2 confirmed that the D842V mutant protein was not inhibited by sorafenib, imatinib or dasatinib at concentrations up to 1000 nM, in contrast to FIP1L1-PDGFRα itself or the T674I mutant. Intriguingly, FIP1L1-PDGFRα D842V cells are significantly less sensitive to dasatinib than PDGFRα D842V expressing cells. Finally, an ENU-mutagenesis screen indeed identified this mutant as a major sorafenib resistant mutant. In summary, this case represents the fifth reported case of acquired resistance to imatinib in FIP1L1-PDGFRA positive CEL. Our data illustrate the efficacy of sorafenib against FIP1L1-PDGFRα T674I as a single agent in vivo. Yet, selection of secondary sorafenib resistant clones is likely to occur, as has also been observed in imatinib resistant CML treated with second line tyrosine kinase inhibitors. While FIP1L1-PDGFRα D842V is a novel panresistant mutation in CEL, the PDGFRα D842V mutation is a known activating mutation of PDGFRα and causes primary imatinib resistance in a small percentage of gastro-intestinal stromal tumors. The homologous KIT D816V mutation in systemic mastocytosis is also associated with imatinib resistance. Of note, the latter two mutations respond better to dasatinib than FIP1L1-PDGFRα D842V. Our observation highlights the difficult challenge of treating resistant mutations and provides a basis for further proactive development of inhibitors with activity against sorafenib resistance mutants.

Monitoring response to imatinib by quantitative real-time polymerase chain reaction (RQ-PCR) in chronic phase, chronic myeloid leukemia patients in complete cytogenetic remission

18013 Background: Chronic myeloid leukemia (CML) landscape has radically changed since treatment with imatinib. As the majority of CML patients (pts) treated with imatinib achieve a complete cytogenetic remission (CCyR), molecular studies that measure the level of bcr/abl transcripts to determine minimal residual disease are mandatory. The degree of reduction of total leukemia cell mass by imatinib as measured by RQ-PCR correlates with progression-free survival. Methods: We monitored bcr-abl transcript levels by RQ-PCR in 169 CML pts in chronic phase (CP) that achieved CCyR with a median follow up of 15 months (range 6–26). Median age was 51 (range 18–82), 83 pts (49%) were newly diagnosed and 86 (51%) had been previously treated with interferon-alfa; 54% had low sokal score, 29% intermediate and 17% were high risk. At baseline, pts were evaluated by FISH and RQ-PCR, transcript quantification by RQ-PCR was measured every 6 months from baseline at 6, 12 and 18 months. Results: At present 78 pts completed 4 evaluations at month 0, 6, 12 and 18. Mayor molecular response (MaMR: > 3 log red in bcr-abl transcript levels) was obtained in 62% at month 18 compared to 45% obtained at study initiation. Minor (Mi)MR at month 18 was of 38% vs 50% at initial evaluation. The pts could be divided into three groups according to molecular responses: 1- in 34 pts transcript levels continued to decline during the observation period, 2- in 38 pts transcript level reached a plateau and 3- in 6 pts transcript levels increased. From pts who obtained MiMR at baseline, 54% showed decrease in transcript levels obtaining MaMR in 44% of pts. Nine pts changed treatment to a second line tyrosine kinase inhibitor, causes were: lost CCyR: 3, lost hematologic response: 1, molecular relapse: 4 and intolerance to treatment: 1. Conclusion: The pattern of residual disease after achieving CCyR on imatinib is variable: some patients show progressive reduction of transcript levels, others reach a plateau showing stable transcript levels and other show rising levels of bcr-abl defining a group of patients were therapeutic decisions are mandatory. No significant financial relationships to disclose.

Nilotinib and donor lymphocyte infusion in the treatment of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) relapsing after allogeneic stem cell transplantation and resistant to imatinib

Prognosis of patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) relapsing after allogeneic stem cell transplantation (SCT) is dismal. Immunotherapy with donor lymphocyte infusion (DLI) and imatinib are rarely and/or transiently effective. Here we describe the case of a patient with imatinib-resistant post-transplant relapse of ALL, who received a combination of standard dose nilotinib and monthly DLI infusion. Therapy was well tolerated and the patient achieved and maintained a complete molecular remission. Our case provides a rationale for the combined use of a second line tyrosine kinase inhibitor and DLI in the treatment of relapsed Ph+ ALL.