Transplantation For Chronic Myeloid Leukemia Research Articles

Primary distal femur T-cell lymphoma after allogeneic haematopoietic stem cell transplantation for chronic myeloid leukaemia: A rare case report and literature review

Post-transplant lymphoproliferative disorders originating from T lymphocytes are a rare complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) that are not usually associated with Epstein-Barr virus infection. A male patient diagnosed at the age of 15 years with chronic myeloid leukaemia (in the chronic phase) was initially treated with oral hydroxyurea. The disease entered an accelerated phase when the patient was 22 years old. Complete remission was achieved after one course of homoharringtonine and cytarabine. The patient then underwent human leucocyte antigen-matched sibling donor allo-HSCT. Just over 6.5 years after the allo-HSCT, a second primary tumour was located in the distal femur and diagnosed as T-cell non-Hodgkin's lymphoma (stage IV, group B). This was treated with various chemotherapy and radiotherapy regimens, but the outcomes were poor and the disease progressed. The T-cell lymphoma invaded many sites, including the skeleton, spleen and skin, and the patient died within 8 months of the diagnosis. This current case report highlights the need for the early detection and prevention of subsequent primary malignancies after allo-HSCT.

Development of mycosis fungoides after bone marrow transplantation for chronic myeloid leukaemia: transmission from an allogeneic donor

We report on a patient who developed donor-derived cutaneous T-cell lymphoma (CTCL) 4 years after successful treatment of chronic myeloid leukaemia with an allogeneic bone marrow transplant. The patient developed an eczematous rash unresponsive to topical therapy and immunosuppression. When CTCL was diagnosed in the recipient, his sibling donor had been attending his local dermatology unit with a maculosquamous rash, which proved subsequently to be mycosis fungoides. An identical pattern of donor and recipient clonality assessment and T-cell receptor gene sequencing indicated that the CTCL was probably transmitted in the bone marrow harvest. This suggests that CTCL cells circulate in the marrow at an early subclinical stage in this disease. This is the second case of donor-derived CTCL reported to date.

Lacking Of Missing Killer-Immunoglobulin-Like Receptor Ligand In Recipients Can Predict Better Prognosis After HLA-Mismatched/Haploidentical Transplantation Without T Cells Depletion In Vitro In Chronic Myeloid Leukemia Patients

IntroductionHLA-mismatched/haploidentical stem cell transplantation (SCT) is a feasible therapeutic option for advanced hematologic malignancies patients who lack an HLA-matched related or unrelated donor. The effect of NK alloreactivity in HLA haploidentcial SCT is still under debate and in particular in transplantation for chronic myeloid leukemia (CML) the data are very limited and with conflicting outcome.The goal of this study was to explorethe predictive roles of missing self model in our HLA-mismatched/haploidentical transplantation without T-cell-depletion in vitro in chronic myeloid leukemia patients, and to develop a simple algorithm on the basis of recipients and donor HLA-C and HLA-Bw4 gene content that can be used today to identify HLA-mismatched donors who will associated withbetter prognosis in T cell¨Creplete transplants. MethodsWe studied the HLA genotype of 78 donor-recipient pairs and the KIR genotype of their donor, who underwent unmanipulatedHLA-mismatched/haploidentical transplantation without T cells depletion in vitro during 2003-2009 in our center. To applythe missing ligand model, the first step was to divide ourdonor-recipient pairs into 2 groups according to the number of KIR ligand indonor and recipient, ie, 3 KIR ligands (“without missing self”) versus fewer than 3(“with missing self”). Meanwhile, to apply the KIR ligand-ligand model, donors who were classified as NK alloreactive against their recipientstermed KIR ligand mismatched donors throughout, possessedHLA class I KIRligand(s) which were missing in the recipients. ResultsAmong the 78 pairs of donor-recipients, 65 and 13 recipients receivedHLA¨Cmismatched/haploidentical transplants from “with missing self (R-L mismatch)” and “without missing self (R-L match)” donors, respectively. Using Ligand-ligand model, 59 and 19 recipients received haploidentical transplantation from “KIR ligand matched (L-L match)” and “KIR ligand mismatched (L-L mismatch)” donors, respectively. In contrast to Perugia's KIR ligand-ligand mismatched model or Handgretinger's KIR missing self model between donor-recipient pairs, we found that the 10-year disease free survival(DFS) rate were higher in patients received transplantation from “without missing self (R-L match)” donorscompared with those from “with missing self (R-L mismatch)” (92.3±7.4% vs. 55.2%±6.2%, p=0.024, Figure1A) , especially in high risk CML patients (100% vs. 37.2%±8.6%, p=0.029, Figure1B). When combined the above missing self model and Ligand-ligand model together, patients were subgrouped as receiving graft from “without missing self and without KIR ligand mismatch (R-L match and L-L match)” (n=13), “with missing self and without KIR ligand mismatch (R-L mismatch and L-L match)” (n=47), and “with missing self and with KIR ligand mismatch (R-L mismatch and L-L mismatch)” (n=18), respectively. Cox regression model showed the 10-yearDFSwas best predicted by the combination of missing self model and Ligand-ligand modelbetween recipients and donors pairs (HR 2.205(1.113-4.368), p=0.023, Figure1C). Meanwhile, donor KIR 2DS5 positive associated with higher DFS post-transplantation (84.2±8.4% vs. 56.8±7.7%, p=0.045) in CML patients. However, donor KIR haplotype B have no effect on DFS and overall survival after allogeneic hematopoietic stem cell transplantation for multiple myeloma [Display omitted] ConclusionsThese data indicate thatpoor prognosis after transplantation is associated with the missing self and KIR ligand mismatch in recipients and T cell alloreaction may play apredominant role in this model.Based on recipients and donor HLA-C and HLA-Bw4 gene content, it could befeasible to identify HLA-mismatched donors who will predict the better prognosis in CML patients post T cell-replete transplant. Disclosures:No relevant conflicts of interest to declare.

Stem Cell Transplantation for Chronic Myeloid Leukemia (CML): Current Indications and Perspectives

The introduction of tyrosine kinase inhibitors (TKIs) has reduced the indications for allogeneic stem cell transplants (SCT) in patients with chronic myeloid leukemia (CML) from 1500/year in 2000 to approximately 500/year in 2010. The recently updated indications by the European Leukemia Network include advanced-phase CML and nonresponders to second-line TKIs. Changes in transplant programs, over the past decade, have resulted in a significant reduction in transplant related mortality and this has expanded the transplant option to older patients, who may be eligible for SCT. Transplantation for blastic phase CML remains a challenge due to the high rate of post-transplant relapses. Thus, in view of this issue, several studies of TKIs after allogeneic SCT have been undertaken with encouraging results. In conclusion, allogeneic SCT remains a therapeutic option for selected patients with CML and is currently being integrated with the use of TKIs both before and after transplantation.

Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors- What are the Limitations?

The treatment strategies for chronic myeloid leukemia have changed dramatically with the advent of tyrosine kinase inhibitors. Since they provide an excellent opportunity for complete cytogenetic and molecular remissions, they are recommended as a first line therapy. Although a small fraction of patients has been reported to remain in molecular remissions after discontinuing of tyrosine kinase inhibitors, there is an increased likelihood of disease relapse after these drugs are discontinued. Therefore, allogeneic stem cell transplantation remains the only cure at present. However, toxicity of preparative regimens, development of graft versus host disease, infectious complications, and increased rates of relapse in advanced phases of the disease limit the safety and efficacy of this approach. This review highlights the major limitations of transplantation and the areas of studies required to improve the clinical outcomes.

Long-Term Follow-up Results Over 7 Years for Survival, and Safety with Imatinib Mesylate Accompany with Allogeneic Transplantation for Chronic Myeloid Leukemia

Abstract 4529 Objective:To observe the efficacy and safety of imatinib mesylate (IM) accompany with allogeneic transplantation for chronic myeloid leukemia (CML). Methods:During the period from January 2003 to August 2011,we retrospectively observed 95 patients with CML receiving IM for a minimum of 4 months before allogeneic hematopoietic stem cell transplantation (HSCT). Patients with advanced CML received IM from 3 month after transplantation for 12 months. Results:Among 95 enrolled patients (CML-CP 76, CML-AP 10, CML-BP 9), types of transplantation: sib-matched HSCT 64, unrelated-HSCT 19, haplo-HSCT 12. For the whole patients, 7 year overall survival (OS) is 80.5%, and disease free survival (DFS) is 74.5%. Complete hematologic response (CHR) is 93.6%, complete cytogenetic response (CCR) is 84.5%, major cytogenetic response (MCR) is 60.3% at 7 year. For CML-CP1, OS is 83.2% and CML-AP/BC is 33.3% (P<0.05). Compared patients of advanced CML achieving CP2 after IM and with no CP2,the former has better results of CCR or MCR, OS and PFS (P<0.05). The total treatment related mortality (TRM) is 16.8%. Cox multivariate regression analysis of prognostic factors indicates that status of CML and severe acute graft-versus-host disease (aGVHD III-‡W) retain independent predictive value. No increase in rates of serious adverse events was observed with continuous use of IM for up to 7 years. Conclusions:For chronic myeloid leukemia, combining with imatinib mesylate and allogeneic transplantation is a good strategy, with favorable long-term follow-up results and acceptable TRM, especially for the patients with advanced CML. Disclosures:No relevant conflicts of interest to declare.

International Consensus Criteria for Tyrosine Kinase Inhibitor Response and Outcome of Allogeneic Stem Cell Transplantation for CML

AbstractAbstract 1997▪▪This icon denotes a clinically relevant abstract BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients with chronic myeloid leukemia (CML), and is reserved for those who do not respond optimally to tyrosine kinase inhibitors (TKI). Baccarani et al summarized international consensus criteria (ICC) for response to imatinib in first chronic phase (CP) based on time to response; these criteria are used to select alternative therapies including second generation TKIs or HSCT for less than optimal responses. (Baccarani M, et al.J Clin Oncol. 2009; 27:6041–6051). Patients in blast crisis (BC) or accelerated phase (AP) proceed for HSCT if eligible, regardless of optimal response. The prognostic influence of ICC stratification prior to transplant is unknown. We hypothesized the ICC would influence progression after HSCT in patients with CML; in this study we report the impact of this score on transplant outcomes. Patients and MethodsWe performed a retrospective review of patients with CML who underwent a reduced intensity conditioning treatment with busulfan/fludarabine/ATG ± imatinib followed by HSCT. From 1/2000 to 5/2012, 104 patients underwent a matched unrelated or related allogeneic HSCT at the M.D. Anderson Cancer Center. The ICC was applied to patients prior to transplant to denote optimal, suboptimal, or failure of response to a TKI. Demographic and disease-related data were collected, as well as transplant-related covariates. Outcome of interest was progression free survival (PFS) and overall survival (OS), which was estimated using the Kaplan-Meier method. ResultsPatient characteristics are summarized in Table 1, and analysis in Table 2. 36/104 patients received a conditioning treatment containing imatinib and PFS was not statistically different. With median follow up of 36 months (1–126), 62 patients are alive and 30 patients have progressed. Of the 42 deaths, 27(64%) were primarily attributed to leukemia relapse, 3 (9%) infection, 6(17%) graft versus host disease and 6(10%) of other causes. OS was 50% (38–61%) at last follow up and 55% (44–65%) at 36 months. By multivariate analysis, factors predicting progression were: disease status CP1 vs >CP1 (p=0.001) and failure vs optimal/suboptimal response to TKI as defined by ICC (p=0.02). Optimal or suboptimal response defined by ICC was not an independent predictor of the rate of disease progression, OS, or PFS. 77% of patients in the most advanced disease group (AP2/BC/≥CP3) failed to respond to a TKI compared with 44% of patients in CP1 and intermediate group (CP2/AP1/CE), (p=0.006). Age >50 yrs was associated with a trend for higher disease progression, and lower OS and PFS but did not reach significance. There was no impact of ICC stratification in first chronic phase patients; only one patient died or progressed despite 48% identified as failure based on ICC score. ConclusionIn this single center study with long follow up, we demonstrated ICC score is strongly correlated with disease status at transplant. The latter factor remains the most significant predictor of outcomes. Patients transplanted in first chronic phase have a low rate of progression with allogeneic hematopoietic transplantation regardless of response to TKI therapy based upon ICC score.Table 1ICC Score prior to HSCTOptimal (n=21/19%)Suboptimal (n=29/29%)Failure (n=53/52%)Diagnosis to HSCT (yrs)2.5 (0.3–20)2 (0.4–26)2.8 (0.2–17)Age at HSCT (yrs)44 (14–66)47 (19–64)44 (21–69)Disease Status Correlated to ICCCP1 (23/23%)5/22%7/30%11/48%%CP2 (39/38%)12/31%13/33%%14/36%≥CP3 (5/5%)2/40%1/20%2/40%AP1 (10/10%)0/0%4/40%6/60%AP2 (7/7%)0/0%1/14%6/86%BC (10/9%)1/10%0/0%9/90%CE (9/8%)1/11%3/33%5/56%Imatinib vs 2nd gen TKI pre HSCT11 (52%)/1017 (58%)/1227 (50%)/26Table 2PFSOSDisease Status Groupn=104HR at 3 yr95% CIpHR at 3 yr95% CIpCP1230.030.004–0.20.0010.040.006–0.330.003CP2/AP1/CE590.30.1–0.5<0.0010.30.2–0.70.001AP2/≥CP3/BC221.01.0Multivariate Analysis adjusting for age & disease statusn=1043 y % KMHRp3 y % KMHRpCP12395%0.10.0295%0.070.01not CP1/≤50 yrs4952%ReferenceReference55%ReferenceReferencenot CP1/>50 yrs3233%1.70.133%1.80.07CP = Chronic phase; AP = Accelerated phase; BC= Blast crisis; CE = clonal evolution; HR= Hazard ratio; KM = Kaplan Meier. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Costs and Cost-Effectiveness of Allogeneic Stem Cell Transplantation in Children Are Predictable

The overall costs of pediatric stem cell transplantation (SCT), including donor search and costs during the first year post-SCT, were calculated in a cohort of 141 consecutive children undergoing SCT in a single institution. Costs were correlated with patient and transplantation characteristics and with a risk score for transplantation-related mortality. Cost-effectiveness was calculated based on the overall cost per surviving patient. Life-years gained were extrapolated from overall survival, and the costs per expected life-year gained were calculated. The overall median cost was €136,382 (175,815$), with a wide range, of €26,897 (34,679$) to €601,348 (775,343$). Increased costs were significantly associated with age, use of donors other than matched siblings, and advanced disease. There was a strong correlation of costs with a simple transplantation-related mortality risk score; median total costs were €89,550 (115,463$) for a score of 0, €127,349 (164,179$) for a score of 1, €156,578 (201,861$) for a score of 2, and €274,915 (354,499$) for a score of 3 (P < .001). Cost-effectiveness decreased with increasing transplantation-related mortality risk score; costs per survivor increased from €93,209 (120,200$) for a score of 0 to a maximum of €1,216,348 (1,568,579$) for a score of 3. Costs associated with pediatric SCT vary substantially; however, the combination of variables such as age, disease, and donor type is predictive of costs and cost-effectiveness. Costs per life-year gained are within the broadly accepted range in life-threatening hemato-oncologic diseases, even in the most cost-intensive patient cohort.

Hematopoietic cell transplantation for chronic myeloid leukemia in developing countries: perspectives from Latin America in the post-tyrosine kinase inhibitor era

Tyrosine kinase inhibitors (TKIs) are currently the first line treatment for chronic myelogenous leukemia (CML) in countries with high and intermediate-high gross national income. Hematopoietic cell transplantation (HCT) in these countries is considered salvage therapy for eligible patients who failed TKI or progress to advanced disease stages. In Latin America, treatment for CML also changed with availability of TKI in the region. However, many challenges remain, as the cost of this class of medication and recommended monitoring is high. CML treatment practices in Latin America demonstrate that the majority of patients are treated with TKI at some point after diagnosis, most commonly imatinib mesylate, but still TKI can only be used after interferon failure in some countries. Other treatment practices are different from established international guidelines, outlying the importance of continuing medical education. Allogeneic HCT is a treatment option for CML in this region and could be considered a cost-effective approach in a small subset of young patients with available donors, as the overall cost of long-term non-transplant treatment may surpass the cost of transplantation. However, there are many challenges with HCT in Latin America such as access to experienced transplant centers, donor availability, and cost of essential drugs used after transplant, which further impacts expansion of this treatment approach in patients in need. In conclusion, Latin American patients with CML have access to state of the art CML treatment. Yet, drug costs have a tremendous impact on developing health systems. Optimization of CML treatment in the region with appropriate monitoring, recognizing patients who would be transplant candidates, and expanding access to transplantation for eligible patients may curtail these costs and further improve patient care.

Predicting relapse prior to transplantation in chronic myeloid leukemia by integrating expert knowledge and expression data

Selecting a small number of signature genes for accurate classification of samples is essential for the development of diagnostic tests. However, many genes are highly correlated in gene expression data, and hence, many possible sets of genes are potential classifiers. Because treatment outcomes are poor in advanced chronic myeloid leukemia (CML), we hypothesized that expression of classifiers of advanced phase CML when detected in early CML [chronic phase (CP) CML], correlates with subsequent poorer therapeutic outcome. We developed a method that integrates gene expression data with expert knowledge and predicted functional relationships using iterative Bayesian model averaging. Applying our integrated method to CML, we identified small sets of signature genes that are highly predictive of disease phases and that are more robust and stable than using expression data alone. The accuracy of our algorithm was evaluated using cross-validation on the gene expression data. We then tested the hypothesis that gene sets associated with advanced phase CML would predict relapse after allogeneic transplantation in 176 independent CP CML cases. Our gene signatures of advanced phase CML are predictive of relapse even after adjustment for known risk factors associated with transplant outcomes.

Analysis of non-HLA genomic risk factors in HLA-matched unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia

Allogeneic hematopoietic cell transplantation is the main curative therapy for patients with chronic myeloid leukemia who do not respond to tyrosine kinase inhibitors. It has been proposed that non-human leukocyte antigen gene polymorphisms influence outcome after hematopoietic cell transplantation and could be used alongside traditional patient-donor and transplant characteristics to create a recipient risk profile associated with allogeneic hematopoietic cell transplantation. A previous study from the European Group for Blood and Marrow Transplantation showed that the absence of recipient tumor necrosis factor receptor II, absence of donor interleukin 10 ATA/ACC and presence of donor interleukin 1 receptor antagonist allele 2 genotypes were associated with decreased survival and increased non-relapse mortality in adult patients with chronic myeloid leukemia undergoing myeloablative human leukocyte antigen-identical sibling transplantation. To explore these associations in unrelated donor transplantation, these polymorphisms were genotyped in 383 adult patients with chronic myeloid leukemia who underwent hematopoietic cell transplantation from unrelated donors matched for 10/10 human leukocyte antigens. The polymorphisms were not associated with overall survival, non-relapse mortality, relapse or acute graft-versus-host disease in the unrelated donor cohort. Comparison of the unrelated donor and human leukocyte antigen-identical sibling cohorts showed differences in survival and clinical characteristics. We did not confirm that non-human leukocyte antigen polymorphisms were associated with outcomes in myeloablative unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia, possibly because of the strong association between clinical variables and outcome which masked more subtle genetic effects.

Impact of Hemochromatosis Gene (HFE) Polymorphisms and Iron Overload on Outcome of Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukemia

Impact of Hemochromatosis Gene (HFE) Polymorphisms and Iron Overload on Outcome of Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukemia

Long-Term Experience with Allogeneic Bone Marrow Transplant (BMT) in Chronic Myeloid Leukemia

Abstract 4582 Introduction:Introduction of imatinib mesylate has changed the approach towards bone marrow transplantation in Chronic Myeloid Leukemia (CML). Historically considered as a curative therapeutic option, with a probability of disease free survival ranging from 40 to 60%. Its indicated use has been restricted to patients with treatment failure to prior tyrosin-kinase inhibitors or blast crisis. Objective:To assess the outcome of patients with CML who undergo BMT Materials and methods:66 patients who underwent allogeneic BMT between the years 1994 and 2011 in two health care facilities were analyzed. 63 (93%) were performed between 1994 and 2005. At the time of transplantation, patient status was: 56 patients in 1st Chronic Phase and 10 in advanced phases. Fourteen patients received Unrelated Donor BMT and 37 had Related Donor BMT. Transplant risk was assessed, based on the European Bone Marrow Transplantation (EBMT) score (sc). The conditioning regimens which were used included: for patients in chronic phase, cyclophosphamide (Cy) and busulfan (Bu) and for patients in accelerated phase etoposide (VP 16) was added to the previous regimen, and for unrelated donors BuCy + ATG or alentuzumab was used. Prophylaxis for Graft vs Host Disease (GVHD) was performed with a two-drug regimen (cyclosporine, methotrexate), with or without methylprednisone. Result:66 patients were recorded (28 female/38 male), with a mean age of 35 years at the time of transplantation (range 8–55). The source of Stem Cell was bone marrow in 60 patients and peripheral blood in 6 patients. 43% of patients developed GVHD: (29 patients) according to clinical criteria established by the European Cooperative Group. Overall Survival (OS) was 50% with a mean follow-up of 48 months. Analyzed according to the EBMT risk score, OS was 64% in the 0–2 score group and 31% in patients with a 3–5 score. Procedure-related mortality was 16%, and the most frequent causes included: hepatic veno-occlusive disease, infections, GVHD, and graft failure. Conclusions:BMT in patients with CML has been substantially reduced since the introduction of tyrosin-kinase inhibitors. In our experience, this shows its healing potential with an extended follow-up and a prolonged survival. Disclosures:No relevant conflicts of interest to declare.

The Majority of Patients Receiving Donor Lymphocyte Infusions for Relapsed Chronic Myeloid Leukemia Remain PCR Positive Despite Maintaining Long-Term Remission,

Abstract 4103Donor lymphocyte infusions (DLI) produce molecular remission in the large majority of chronic myeloid leukaemia (CML) patients who relapse after allografting. Although response to DLI is associated with long-term clinical remissions, we asked whether minimal residual disease could still be detected. We identified 116 patients who had received escalating doses of donor lymphocytes between 1995 and 2010 for molecular, cytogenetic or haematological relapse following allogeneic hematopoietic stem cell transplantation for CML. These patients had serial monitoring of their response by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR). 84 patients had achieved a complete molecular remission (CMR) (defined by 2 consecutive negative PCR), however 79 (94%) of these subsequently became positive again. All patients who achieved a complete molecular remission were allocated to 3 categories: (1) “persistently negative” or a single low level positive result (n=15 (18%); (2) “fluctuating low-level positive”, who had multiple positive results, but never more than 2 consecutive positive results (n=34 (40%)); and (3) “persistently low-level positive” (n=35(42%)), and the rates of relapse were compared in the three groups. The overall probability of relapse (defined by the initial molecular relapse criteria) at 10 years was low in all three groups (6.7%), and there was no significant difference in each category: 0%, 4.2% and 10.3% respectively (P=0.372) (figure 1), with no survival difference in the three groups. Furthermore, of the 32 patients who did not achieve a CMR, 11 achieved a fall in PCR to <0.1 (major molecular remission (MMR)) following completion of their DLI protocol and had a non-inferior survival to those who achieve a CMR, in contrast to those who did not satisfy either of these criteria, and had a significantly inferior survival (p<0.01) (figure 2). We conclude that the majority of patients who respond to DLI do not remain PCR negative, but low-level positive results do not predict relapse. This suggests that, although DLI does not completely eradicate the disease, it exerts a highly effective long-term disease control. The data presented also raises the question of whether persistent PCR negativity should be unequivocally pursued, or whether a threshold of MMR may be adequate. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Improved outcome following allogeneic stem cell transplantation in chronic myeloid leukemia is associated with higher expression of BMI-1 and immune responses to BMI-1 protein

BMI-1 and EZH2 are polycomb group (PcG) proteins which maintain self-renewal of stem cells, and are overexpressed in leukemia. To investigate the potential of PcG proteins as leukemia-associated antigens, and targets for graft-versus-leukemia (GVL) effects, we studied cells from 86 chronic myeloid leukemia (CML) patients and 25 HLA-A*0201+ sibling donors collected prior to allogeneic stem cell transplantation (SCT). Although BMI-1 overexpression in CD34+ cells of CML patients treated with pharmacotherapy is associated with poor prognosis, we found, conversely, that in CML patients treated with SCT, a higher expression of BMI-1, and correspondingly lower expression of its target for repression, CDKN2A, is associated with improved leukemia-free survival. Cytotoxic T lymphocyte (CTL) responses to BMI-1 peptide were detected in 5 of 25 (20%) donors, and 8 of 19 (42%) HLA-A*0201+ CML patients. BMI-1 generated more total and high avidity immune responses, and was more immunogenic than EZH2. PcG-specific CTLs had memory phenotype, were readily expanded in short-term cultures, and were detected post-SCT in recipients of PcG-specific CTL-positive donors. A higher BMI-1 expression in CML CD34+ progenitors was associated with native BMI-1 immune responses. These immune responses to PcG proteins may target leukemia stem cells and have relevance for disease control by GVL.

Three decades of transplantation for chronic myeloid leukemia: what have we learned?

AbstractLast year marked 30 years of hematopoietic stem cell transplantation as a curative treatment of chronic myeloid leukemia (CML). Initially studies used stem cells from identical twins but techniques rapidly developed to use cells first from HLA-identical siblings and later unrelated donors. During the 1990s CML became the most frequent indication for allogeneic transplantation worldwide. This, together with the relative biologic homogeneity of CML in chronic phase, its responsiveness to graft-versus-leukemia effect and the ability to monitor low level residual disease placed CML at the forefront of research into different strategies of stem cell transplantation. The introduction of BCR-ABL1 tyrosine kinase inhibitors during the last decade resulted in long-term disease control in the majority of patients with CML. In those who fail to respond and/or develop intolerance to these agents, transplantation remains an effective therapeutic solution. The combination of tyrosine kinase inhibitors with transplantation is an exciting new strategy and it provides inspiration for similar approaches in other malignancies.

Impact of Prior Second-Generation Tyrosine Kinase Inhibitors on the Outcome of Hematopoietic Stem Cell Transplantation for Chronic Myeloid Leukemia

AbstractAbstract 2267Prior to the introduction of the tyrosine kinase inhibitors (TKI) into clinical practice, the only curative therapy for chronic myeloid leukaemia (CML) was allogeneic hematopoietic stem cell transplantation (HSCT). HSCT is nowadays recommended for patients in accelerated phase, blastic phase or with the T315I mutation and for patients who experience second-line TKIs (TKI2) failure or intolerance. The impact of TKI2 for CML on the results of subsequent HSCT has not yet been clearly established, although preliminary data does not suggest an increase of non relapse mortality (NRM) in patients previously treated with these agents. To assess whether exposure to TKI2s before HSCT adversely affects outcome, we retrospectively analyzed 31 patients with CML reported to the French registry for HSCT between January 2001 and December 2008 who received a first HSCT for imatinib resistant or intolerant CML subsequently treated with either nilotinib or dasatinib or both.The median age at diagnosis was 39.8 years (range, 19–61). At the start of TKI, 15 (48%) patients were in chronic phase, 12 (39%) patients were in accelerated phase and 4 (13%) patients were in blast crisis. For chronic phase patients, 6 (40%) patients were classified as low Sokal risk, 7 (46%) as intermediate risk, and 2 (14%) as high risk. After imatinib failure (among the 27 patients in chronic or accelerated phase at diagnosis), 21 and 6 patients received dasatinib and nilotinib, respectively. Among these patients, 9 patients received a third line therapy, including 5 sequential therapies with both drugs. The best response to the second and third-line treatments with TKI2 was a complete molecular response in 2 patients, a major molecular response in 2 patients, a complete cytogenetic response (CCR) in 7 patients, a complete hematologic response in 14 patients and no response in 2 patients. 14 patients eventually failed TKI2 treatment because of resistance, whereas 8 were considered as intolerant. Of 14 patients who developed resistance to TKI2, 2 had a mutation identified (T315I in both cases).Median interval from diagnosis to HSCT was 19 months (range, 3–151). At time of transplant, 21 patients were in chronic phase, 10 in accelerated phase and none in blast crisis. 19 patients received a graft from an unrelated donor whereas 12 a match related donor. Stem cell source was peripheral blood, bone marrow or cord blood in 20, 8 and 3 patients, respectively. The conditioning regimen was myeloablative in 21 patients combining either TBI and cyclophosphamide (9 patients) or high dose IV busulfan and cyclophosphamide (12 patients), and a RIC for 10 patients. All patients engrafted successfully: median time to neutrophil and platelet recovery was 18 days and 21 days respectively. Grade 2–4 acute graft-versus-host disease (aGVHD) was observed in 11 (37.9%) patients; grade 3–4 aGVHD occurred in 6 (20.6%) patients. Chronic GVHD was observed in 15 (60%) of 25 patients alive after day 100. The median follow-up after HSCT is 27 months (range, 1.2–50.2). At time of analysis, 11 (35%) patients died, 7 (22.5%) from NRM and 4 (12.5%) from progression of disease. NRM was due to infection (3 patients), GVHD (2 patients), post transplant lymphoma disease (1 patient) and unknown cause (1 patient). The 1-year overall survival (OS) was 79.2% (95% CI, 64,3-94,1%) and the estimated 2-year OS was 55,5% (95% CI, 35,0-75,9%). One-year relapse and NRM rates were respectively 10,3% (95% CI, 2.5–24.6%) and 19.1% (95% CI, 6.7–36.2%). In univariate analysis, no variable had a significant impact on outcome among Sokal score, disease phase at diagnosis, Grathwol score, age at HSCT, time from diagnosis to HSCT, or quality of response before HSCT. In a multivariate analysis, only quality of response (at least better than CCR) was significantly associated with a better outcome in terms of OS (p=0.0459, HR=0.17, 95% CI=0.03-0.97).In conclusion, TKI2 prior to HSCT did not result in an increased risk of NRM. However, our observation that patients in cytogenetic or molecular response at time of HSCT have a significant better outcome underscores the importance of a stringent prospective molecular monitoring under TKI2 therapy and the need for prognostic factors of response under TKI2. Such elements could help to better define after initiating TKI2 treatment patients that could really benefit from HSCT and the best timing of the procedure. Disclosures:No relevant conflicts of interest to declare.

Minimal Residual Disease following Allogeneic Hematopoietic Stem Cell Transplantation

Minimal residual disease (MRD), both before and after transplantation, is a clinically important yet relatively poorly defined aspect of allogeneic hematopoietic stem cell transplantation (alloHSCT). The clinical relevance of MRD in the context of alloHSCT has been demonstrated by its association with the development of clinical relapse. However, with the possible exception of chronic myeloid leukemia (CML), the specific techniques, timing, frequency, and clinical utility, relative to improvement in patient outcomes, for monitoring MRD in the setting of alloHSCT has yet to be clearly defined. A concise overview of monitoring techniques for detecting MRD, as well as treatment strategies and biological and clinical research initiatives for MRD suggested by the National Cancer Institute First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation, is covered in this article.

Genome gains at chromosome 21q21/22 segment leads to co‐amplification of Down Syndrome Critical Regions and known oncogenes in a case of donor cell‐derived acute myeloid leukaemia following allogeneic sex mismatched umbilical cord blood transplantation for chronic myeloid leukaemia

Genome gains at chromosome 21q21/22 segment leads to co‐amplification of Down Syndrome Critical Regions and known oncogenes in a case of donor cell‐derived acute myeloid leukaemia following allogeneic sex mismatched umbilical cord blood transplantation for chronic myeloid leukaemia

Leukemia Lineage-Specific Chimerism Analysis and Molecular Monitoring Improve Outcome of Donor Lymphocyte Infusions

A retrospective analysis was performed of 118 patients with hematologic malignancies who received donor lymphocyte infusions (DLIs) after allogeneic stem cell transplantation (ASCT). Treatment was either given because of hematologic relapse (n = 44), molecular/cytogenetic relapse (n = 52), or other causes (n = 22). Molecular relapse was in most cases based on leukemia lineage-specific chimerism analysis. Patients with acute leukemia and myelodysplastic syndrome showed a 3-year survival of 42% if DLI treatment was given because ofmolecular relapse, compared to 16% in hematologic relapse (P < .006). In multivariate analysis, there was a correlation between response to DLI and nonhematologic relapse (risk ratio [RR] 3.36, P = .001), chronic graft-versus-host disease (cGVHD) (RR = 1.51, P = .005), and late relapse (RR = 2.06, P = .017). The overall incidences of acute GVHD (aGVHD) grades I-II and grades III-IV aGVHD were 33% and 8.5%, respectively. Probability of cGVHD was 33%. The development of aGVHD or cGVHD did not significantly influence the response of DLI in patients with molecular/cytogenetic relapse. However, the development of cGVHD was significantly associated with a better response in patients with hematologic relapse because only 4 of 29 patients without cGVHD responded compared to 7 of 12 with cGVHD (P = .007). The development of cGVHD increased significantly if DLI was given >12 months after ASCT (46% versus 27%, P = .04). In contrast, time between ASCT and start of DLI treatment had no significant influence on the risk of developing aGVHD. To conclude, monitoring of leukemia lineage-specific chimerism is of utmost importance for DLI response after ASCT.