Transplantation For Chronic Myeloid Leukemia Research Articles

Allogeneic haematopoietic cell transplantation for chronic myeloid leukaemia in Switzerland in the face of rapid development of effective drugs.

Until the year 2000, allogeneic haematopoietic cell transplantation (HCT) was the standard treatment for young and fit chronic myeloid leukaemia (CML) patients. CML was the main indication for allogeneic HCT. The introduction of tyrosine kinase inhibitors changed the treatment of CML patients dramatically. Allogeneic HCT was rapidly replaced by tyrosine kinase inhibitors as first-line treatment for CML, and the indication shifted to the treatment of non-responders, patients intolerant to tyrosine kinase inhibitors and patients whose CML is transforming to the accelerated phase and blast crisis. This paper describes changes in the use of transplantation technology for CML patients in the face of rapid drug development. All patients receiving a transplant for CML between 1997 and 2021 in Switzerland were included in the study. For the purpose of this analysis, time periods were analysed in quinquennia, 1997-2001 (Q1), 2002-2006 (Q2), 2007-2011 (Q3), 2012-2016 (Q4) and 2017-2021 (Q5), as the observation period spanned 25 years. Overall, 239 patients received a transplant. These included 96 in Q1, 56 in Q2, 25 in Q3, 34 in Q4 and 28 in Q5. Patient characteristics changed over time: recent patients were older and had a longer interval from diagnosis to transplantation because of tyrosine kinase inhibitor treatment. However, the proportions of patients receiving transplants during an early versus advanced disease stage differed little. Transplant technology changed, as well. Patients received intensive conditioning regimens less often due to higher age and more commonly had peripheral blood as opposed to bone marrow transplants. However, the type of stem cell donor selected did not differ. In a univariable analysis, there were no significant differences in survival, progression-free survival, non-relapse mortality, relapse incidence or incidences of acute and chronic graft-versus-host disease among the five quinquennia. In a multivariable analysis, older age, donors other than HLA-identical siblings and more advanced disease stage, but not the quinquennium, were associated with higher risk of death. Since the introduction of tyrosine kinase inhibitors haematopoietic cell transplantation has been used less frequently to treat CML. Patients in recent cohorts received transplants at an older age and later in the disease course; despite these higher risks, the outcome of allogeneic HCT has not worsened over time but has not improved, either. As the outcome is worse in advanced phases, it is important to conduct transplants before disease progression. Therefore, patients with advanced disease should be monitored closely and receive transplants in time.

The Role of Molecular or Cytogenetic Response as a Favorable Prognostic Factor Before Hematopoietic Stem Cell Transplantation for Chronic Myeloid Leukemia

Tyrosine kinase inhibitors (TKIs) have revolutionized therapy for patients with chronic myeloid leukemia (CML) over the last two decades. However, some patients still do not achieve an adequate response to these drugs, and hematopoietic stem cell transplantation (HSCT) is indicated in this scenario. We present the results of a 20-year follow-up study of 70 patients who underwent transplantation after TKI failure. The primary objective of the study was to evaluate overall survival (OS) and the secondary objective was to evaluate the outcomes of relapse-free survival (RFS), GVHD-free, relapse-free survival (GFRS) and the incidences of relapse (RI), non-relapse mortality (NRM), acute and chronic GVHD. Median survival was 11 years, with 1-year OS 70% (57.8 to 79.3) and 5-year OS at 57.7% (45.1 to 68.5). The estimated 5-year OS was not different for CP1 (60%) versus advanced stages (45%); P = .60. The degree of response immediately before transplantation was directly associated with worse outcomes [HR 5.89 (1.19 to 29.16); P = .03] for patients with only a hematological response compared with patients with a cytogenetic or molecular response. This study corroborates the potential of HSCT in the scenario of therapeutic failure and highlights the role of molecular response as a potential target to be achieved before transplantation.

The Role of Allogeneic Transplantation in Chronic Myeloid Leukemia in 2023: A Case-Based Concise Review

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), granting patients a life expectancy close to that of the normal population and, in a subset of patients, the possibility to discontinue therapy. Nonetheless, for a not negligible minority of patients, TKIs are not able to control CML. Allogeneic hematopoietic cell transplantation (HCT) has long been a pivotal therapy for CML. At present, allogeneic HCT is considered an option in CML patients diagnosed or progressing to blast phase (BP), for those in chronic phase (CP) resistant to multiple lines of TKI therapy or for those experiencing severe toxicity, mostly hematologic, under TKIs. Moving from real-world cases, we reviewed the results of allogeneic HCT in the setting of advanced-phase CML or failure of TKIs, with a focus on the progresses in transplant technology that has extended transplant options in elderly CML patients and in those lacking a sibling donor, and on the post-HCT strategies for prevention and treatment of disease relapse.

Allogeneic transplantation for chronic myeloid leukemia: I'm not dead yet!

Allogeneic transplantation for chronic myeloid leukemia: I'm not dead yet!

Transplantation in CML in the TKI era: who, when, and how?

Molecular therapy with tyrosine kinase inhibitors (TKIs) has significantly reduced the indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in chronic myeloid leukemia (CML). Treatment-free remission can be obtained in about 50% of patients with an optimal response. However, cure rates up to 90% are restricted to patients receiving HSCT. Timing is essential since HSCT in the early stages of the disease has the best outcome. Patients in a more advanced phase (AdP) than chronic-phase (chP) CML undergo HSCT with suboptimal outcomes, and the gap between chP and AdP disease is widening. First-line therapy should start with first- or second-generation (G) TKIs. Patients failing treatment (BCR-ABL1 transcripts of greater than 10% at 3 and 6 months and greater than 1% at 12 months) should be switched to second-line TKIs, and HSCT should be considered. Patients not responding to 2G-TKI therapy as well as patients in an accelerated phase (AP) or blast crisis (BC) are candidates for HSCT. Therapy resistant BCR-ABL1 mutations, high-risk additional cytogenetic abnormalities, and molecular signs of leukemia progression should trigger the indication for HSCT. Patients who, despite dose adjustments, do not tolerate or develop severe adverse events, including vascular events, to multiple TKIs are also candidates for HSCT. In AdP CML, TKIs do not show long-lasting results, and the outcome of HSCT is less optimal without pretransplant therapy. In these patients the induction of chP2 with TKIs, either alone (AP) or in combination with intensive chemotherapy (BC), followed by HSCT should be pursued.

Пре- и посттрансплантационные факторы, ассоциированные с первичной недостаточностью и тяжелой дисфункцией трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток при хроническом миелоидном лейкозе

Пре- и посттрансплантационные факторы, ассоциированные с первичной недостаточностью и тяжелой дисфункцией трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток при хроническом миелоидном лейкозеPre- and post-transplantation factors associated with primary graft failure and severe poor graft function after allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia

Allogeneic stem cell transplantation for chronic myeloid leukemia in the tyrosine kinase inhibitor era

Allogeneic stem cell transplantation for chronic myeloid leukemia in the tyrosine kinase inhibitor era

Comparison of Outcomes after Myeloablative Versus Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia

▪Background: Allogeneic hematopoietic cell transplantation (alloHCT) is an effective and curative treatment modality for Chronic Myeloid Leukemia (CML), based on the strong graft-versus-leukemia (GVL) effect. The question about the optimal intensity of conditioning regimen of alloHCT for CML for survival outcomes is relevant, even in the era of tyrosine kinase inhibitors (TKIs). However, no comparison has been attempted between outcomes after myeloablative (MAC) and reduced intensity conditioning/non-myeloablative (RIC) regimens prior to alloHCT. Using the database from the Center for International Blood and Marrow Transplant Research (CIBMTR), we tried to answer the question if RIC alloHCT results in similar outcomes as MAC in patients with CML.Methods: We evaluated 1395 CML patients, between the ages of 18 and 60, who received MAC (n=1204) or RIC (n=191) before alloHCT between 2007 and 2014 and were reported to CIBMTR. The disease status at transplant was divided into the following categories: hematologic complete remission (CR), chronic phase 1 (CP1), chronic phase 2 and beyond (CP2+), accelerated phase (AP). Patients in blast phase (BP) at transplant and alternative donor transplants (haploidentical and cord blood) were excluded. The primary outcome was overall survival (OS) after alloHCT. Assuming a 5-year absolute difference of 15% in favor of RIC (relative risk [RR] 1.56), the study had 92% statistical power to detect this difference if it existed.Results: Median follow up of survivors in the MAC and RIC cohorts was 52 and 60 months, respectively. Patient, disease, and transplantation characteristics were similar with a few exceptions (Table 1). The median ages in MAC and RIC groups were 43 and 51 years, respectively. In vivo T cell depletion using anti-thymocyte globulin or alemtuzumab was used less commonly in MAC (22%) than in RIC group (47%). Multivariate analysis (MVA) showed that there was no significant difference in OS between MAC and RIC groups (p=0.87) (Fig. 1). In addition, disease-free survival (DFS) also did not differ significantly between the two groups (p=0.29) (Fig. 2). MVA failed to show any difference in transplant-related mortality (TRM) between MAC and RIC groups (Cox model p=0.95; Fine-Gray model p=0.58) (Fig. 3). In MVA, compared to MAC, RIC was associated with higher risk of relapse within 5 months of alloHCT (HR 1.85, p=0.001), but after that period, RIC patients had a trend toward lower risk of relapse than MAC (HR 0.64, p=0.09) (Fig. 4). Similar results were obtained with Fine-Gray model. The higher risk of relapse early on after RIC could be due to modest cytoreduction allowing relapse before GVL could take effect. The cumulative incidence of chronic GVHD was lower in RIC compared to MAC (HR 0.77, p=0.02). Subgroup analysis evaluating outcomes in patients who were in CP2+ or AP at transplant showed no significant difference in OS, DFS, TRM, or chronic GVHD and essentially mirrored results of the main model. Interestingly, subgroup analysis among those in CP2+ or AP showed that relapse risk was 2.3 times greater in RIC group during the first 5 months (HR 2.33, p=0.002) and afterward, a lower trend was noted (HR 0.39, p=0.10), compared to MAC.Conclusions: Considering no differences in OS and DFS between MAC and RIC alloHCT for CML in the overall cohort and in a pre-defined subgroup analysis restricted to those in CP2+ or AP, we conclude thatRIC alloHCT is an appropriate choice for CML patients less than 60 years of age. The study showed that higher risk of relapse in the first 5 months post-RIC alloHCT did not lead to inferior DFS or OS, indicating effective salvage treatment of the relapse. In addition, a lower incidence of chronic GVHD associated with RIC is an important consideration in deciding the transplant conditioning regimen for CML. [Display omitted] DisclosuresStuart:Cantex: Research Funding; Agios: Research Funding; ONO: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astellas: Research Funding; Celator/Jazz: Research Funding; Bayer: Research Funding; Seattle Genetics: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel Support, Research Funding; MedImmune: Research Funding; Novartis: Research Funding; Amgen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Research Funding.

Granulocytic Sarcoma with Meningeal Leukemia. A Case Report

The case of a 63-year-old woman is presented who developed 18 years after undergoing allogenic bone marrow transplantation for chronic myeloid leukaemia a granulocytic sarcoma localised in the presacral region. Complete radiologic remission was obtained with the administration of imatinib. She developed a metachron granulocytic sarcoma in the right frontal region associated to leptomeningeal infiltration. Complete clinical and near complete radiological remission was obtained with the administration of nilotinib. The patient was finally lost of progression of the frontal and meningeal localisations 45 months after the presentation of the first presacral lesion. Throughout the follow-up no sign of systemic leukaemia was detected.

Stability of the equilibria of a dynamic system modeling stem cell transplantation

This paper provides a complete analysis of the stability of the steady-states for a three-dimensional system modeling cell dynamics after bone marrow transplantation in chronic myeloid leukemia. There are given results for both chronic and accelerated-acute phases of the disease.

The Role of Stem Cells on the Ovarian Failure Induced by Busulfan in Female Albino Rat

AbstractBackground: Many researches about stem cell therapy in premature ovarian failure treatment have been carried out. The adipose tissue has recently been identified as one of the alternative sources of multipotent resident stem cells in humans. One of the most devastating effects of chemotherapy is the damage of the reproductive system, which in young girls and women younger than 40 years of age is frequently associated with premature ovarian failure. Busulfan has a wide range of using as in a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myeloid leukemia and in patients undergoing bone marrow transplantation.Aim of the Study: The aim of the study was to evaluate the effect of administration of adipose tissue derived stem cells on the ovarian failure induced by the busulfan in female albino rats.Material and Methods: 70 female 8 weeks old albino rats were divided into 5 groups. Group I (control Group): They consisted of 20 female albino rats. They were received no treatment and served as untreated control. Group II (adipose tissue derived stem cells treated group): They consisted of 20 female albino rats. They were received adipose tissue derived stem cells (AT-ASCs). They received million and half of million units of AT-ASCs/single dose for each animal I.V. Group III (busulfan treated Group): They consisted of 10 female albino rats. In this group the ovarian failure was induced using busulfan therapy by a dose 2mg for successive 4 days. Group IV (busulfan treated, followed by AT-ASCs treated group): They consisted of 10 female albino rats. In this group the ovarian failure was induced by the same regimen as in group III. After one week of chemotherapeutic treatment, the animals received million and half of million units of AT-ASCs/single dose for each animal I.V. Group V (busulfan treated, followed by AT-AS Cs treated group): They consisted of 10 female albino rats. The rats in this group received the same regimen as group IV but they were sacrificed 4 weeks after the AT-ASCs injection. Biochemical study: Blood samples were taken from all rats from retro-orbital venous plexus and the serum samples were measured for FSH, LH and serum estrogen level using ELISA technique. Paraffin sections for female albino rat ovaries were prepared to be stained with H&E and Masson’s Trichrome stain for Light microscopic study. Specimens of the ovary were also prepared for electron microscopic study.Results: The AT-ASCs induced definite improvement in the histopathological changes associated with busulfan induced ovarian failure. This improvement was marked one week after AT-ASCs treated but after 4 weeks, there was some regression in this improvement.Conclusion: AT-ASCs transplantation can improve the ovarian damage induced by the busulfan. The need for second dose of AT-ASCs is suggested.

Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia in Era of Tyrosine Kinase Inhibitors -a Single Centre Experience from India

Background Transplant remains most curative option for patients with TKI resistant disease or in advanced phase of CML. We retrospectively analyzed transplant outcome of CML patients in era of TKI from our centre. Methods All patients who underwent allogeneic stem cell transplant for CML between Aug 2010 to Sept 2016 were included. Conditioning regimens included Flu-Mel (67.5%), Bu-Cy (10%), Flu- 7.2 Gy TBI (15%), or Flu-treo-2GyTBI (7.5%). For matched sibling (MSD) or unrelated donor (MUD) transplants, GVHD prophylaxes were cyclosporine (CsA) with methotrexate in 26(65%) or mycophenolate(MMF) in 8 (20%) patients respectively . Post transplant cyclophosphamide (PtCy) with CSA / tacrolimus with MMF was used in 6 (15%) patients who underwent haploidentical transplant (HIT) .Disease Risk Index (DRI), HCT-CI and EBMT scores at transplant were calculated for all . Overall survival (OS) was calculated from date of transplant to date of death or last follow up while relapse-free survival (RFS) was calculated till date of molecular relapse (>0.1% BCR-ABL),death or LFU if in MMR. Prognostic factors evaluated were duration from diagnosis to transplant ( 2 years), EBMT score (≤3 vs>3), acute and chronic GVHD, type of transplant and DRI index. Results Median age was 30 years (12-55) of which 30 (75%) were male. TKI failure was the commonest reason for transplant (95%) .T315I mutation was seen in 17.5% of patients . Twenty-six (65%) were in CP, 8 in AP and 6 in BC at diagnosis. The median EBMT and HCT-CI score were 3 and 2 respectively. Twelve (30%) patients had high DRI. MSD transplant was performed in 33 (82.5%), 6 (15%) underwent HIT and 1 MUD transplant. All except 1 patient received PBSC graft. Grade III/IV mucositis and diarrhea were seen in 19 (47.5%) and 4 (10%) patients respectively. Median time to neutrophil and platelet engraftment were 16 and 13.5 days respectively. Incidence of grade III/IV acute GVHD and chronic GVHD was 50% and 60% respectively. At 1 year post transplant >4.5 log reduction (DMR) was attained in 25 (62.5%) while 5 (12.5%) patients were in MMR. Five patients received DLI (3 patients for clinical relapse,2 for slippage of chimerism). Median follow up was 36 months. Non relapse mortality was seen in 8 (20%) patients. (GVHD-7, Myocarditis1). OS and RFS at 5 years were 70 % and 57 % respectively. In multivariate analysis for RFS, EBMT score≤ 3 and time from diagnosis to transplant > 2 years were independent prognostic factors for better RFS. For OS, presence of chronic and absence of acute GVHD were independent prognostic factors for better survival. Conclusion The long term survival in TKI resistant and advanced CML with transplant is promising. Along with other factors, transplant after 2 years from diagnosis was an independent prognostic factor for better survival contrary to transplant within 1 year of diagnosis in the pre TKI era .This may be due to better disease control with advent of TKIs.

Treosulfan, Fludarabine and Cytarabine As Conditioning before Allogeneic Hematopoietic Stem Cell Transplantation

Background: The combination of treosulfan witth fludarabine was successfully introduced into toxicity-reduced conditioning regimens for hematopoietic stem cell transplantation (HCT). However, the risk of post-HCT relapse remains of concern. Here we report for the first time on the results of an individual treatment approach with treosulfan, fludarabin and cytarabine as conditioning for allogeneic HCT in patients with AML, MPN or MDS.Methods: 22 patients were treated with fludarabine 30 mg/m² given on day -6 to day -2, treosulfan 14 g/m² administered on days -4 to day -2 and cytarabin 2g/m² given on days -6 and -5. GvHD-prophylaxis consisted of cyclosporine A and methotrexate or MMF. In addition, antithymocyte globulin was applied in case of an unrelated donor. One patient received bone marrow and the remaining patients received peripheral blood stem cells from matched related donors (9%), matched unrelated donors (73%) or mismatched unrelated donors (18%). All patients were considered to have high risk of relapse because of unfavourable cytogenetic features and/or insufficient or missing response to previous treatment. Three patients (14 %) with CML after blast crisis received the combination because of the reported high relapse rate (46%) after three-day scheduled conditioning with treosulfan [1]. In addition, patients were considered to be ineligible for myeloablative standard conditioning because of multi-morbidity (n = 4; 18% with HCT-CI >2) and/or age >55 years (n = 14; 64%).Results: The median age of patients was 59 (35-68) years. Patients suffered from acute myeloid leukemia (n = 14, 64%), myeloproliferative neoplasia (n = 6, 27%) or myelodysplasic syndrome (n = 2, 9%). The conditioning regime was well tolerated and nearly all patients engrafted and achieved complete donor-type chimerism, except for one who died very early from sepsis. Another patient with underlying myelofibrosis suffered from secondary graft failure on day 100. Two patients developed aGVHD °III/ IV. None of the patients suffered from veno-occlusive disease or severe chronic GVHD. Overall survival and event-free survival at one year reached 60.2% and 59.6%, respectively. Six patients died from infectious disease, two from relapse and one patient from acute GVHD °IV.Conclusion: The combination of cytarabine with the established conditioning of treosulfan and fludarabine is feasible in patients with high risk of relapse and ineligible for myeloablative standard conditioning.Holowiecki J, Giebel S, Wojnar J et al. Treosulfan and fludarabine low-toxicity conditioning for allogeneic 334 haematopoietic stem cell transplantation in chronic myeloid leukaemia. Br J Haematol 335 2008; 142(2): 284-92. DisclosuresHilgendorf:Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Frietsch:Deutsche Krebshilfe: Research Funding. Scholl:Abbivie: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Deutsche Krebshilfe: Research Funding; Alexion: Other: Travel support. Hochhaus:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Casper:Medac: Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding.

Myeloablative vs reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukemia

AbstractAllogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo-HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era.

Allogeneic Haematopoietic Stem Cell Transplantation for Chronic Myeloid Leukaemia in the Era of Tyrosine Kinase Inhibitors

The introduction of tyrosine kinase inhibitors (TKI) has dramatically improved the prognosis of chronic myeloid leukaemia (CML) patients and, therefore, changed the therapeutic scenario of this disease. Before the advent of the first TKI imatinib, allogeneic haematopoietic stem cell transplantation (alloSCT) was the only curative approach for CML, and all patients deemed eligible for transplant were referred to a centre for transplant where possible. Nowadays, with the wide availability of five different TKI, indications to alloSCT have been reduced to only include patients in the advanced phase of CML and those with multiple TKI treatment failures. Nonetheless, even in the TKI era, alloSCT retains its curative potential. Herein, the authors give an overview of the indications to allogeneic transplant for CML and the management of TKI in the pre and post-transplant settings.

Splenic irradiation before hematopoietic stem cell transplantation for chronic myeloid leukemia: long-term follow-up of a prospective randomized study.

In the context of discussions on the reproducibility of clinical studies, we reanalyzed a prospective randomized study on the role of splenic irradiation as adjunct to the conditioning for hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Between 1986 and 1989, a total of 229 patients with CML were randomized; of these, 225 (98%; 112 with, 113 without splenic irradiation) could be identified in the database and their survival updated. Results confirmed the early findings with no significant differences in all measured endpoints (overall survival at 25years: 42.7%, 32.0-52.4% vs 52.9%, 43.2-62.6%; p = 0.355, log rank test). Additional splenic irradiation failed to reduce relapse incidence. It did not increase non-relapse mortality nor the risk of late secondary malignancies. Comforting are the long-term results from this predefined consecutive cohort of patients: more than 60% were alive at plus 25years when they were transplanted with a low European Society for Blood and Marrow Transplantation (EBMT) risk sore. This needs to be considered today when treatment options are discussed for patients who failed initial tyrosine kinase inhibitor therapy and have an available low risk HLA-identical donor.

The role of hematopoietic stem cell transplantation in chronic myeloid leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently recommended as 2nd or 3rd line therapy for patients with chronic myeloid leukemia (CML) in first chronic phase or as salvage for patients with very advanced disease. As a consequence, numbers of HSCT in chronic phase have dropped significantly since the introduction of tyrosine kinase inhibitors (TKI), numbers of transplants in advanced disease to a lesser extent. These current recommendations consider primarily disease risk, defined as failure of TKI therapy; they might need to be adapted. We propose a more balanced appraisal of HSCT for individual patients which should include disease risk, transplant risk, and macroeconomic aspects. HSCT should be integrated into the treatment algorithms from diagnosis and be considered very early at first TKI failure for patients with high disease but low transplant risk. For patients with very advanced disease and high transplant risk in contrast, HSCT might only be recommended in a restricted research setting.

Comparison of Outcomes of Allogeneic Transplantation for Chronic Myeloid Leukemia with Cyclophosphamide in Combination with Intravenous Busulfan, Oral Busulfan, or Total Body Irradiation

Cyclophosphamide (Cy) in combination with busulfan (Bu) or total body irradiation (TBI) is the most commonly used myeloablative conditioning regimen in patients with chronic myeloid leukemia (CML). We used data from the Center for International Bone Marrow Transplantation Research to compare outcomes in adults who underwent hematopoietic cell transplantation for CML in first chronic phase after myeloablative conditioning with Cy in combination with TBI, oral Bu, or intravenous (i.v.) Bu. Four hundred thirty-eight adults received human leukocyte antigen (HLA)-matched sibling grafts and 235 received well-matched grafts from unrelated donors (URD) from 2000 through 2006. Important differences existed between the groups in distribution of donor relation, exposure to tyrosine kinase inhibitors, and year of transplantation. In multivariate analysis, relapse occurred less frequently among patients receiving i.v. Bu compared with TBI (relative risk [RR], .36; P = .022) or oral Bu (RR, .39; P = .028), but nonrelapse mortality and survival were similar. A significant interaction was detected between donor relation and the main effect in leukemia-free survival (LFS). Among recipients of HLA-identical sibling grafts, but not URD grafts, LFS was better in patients receiving i.v. Bu (RR, .53; P = .025) or oral Bu (RR, .64; P = .017) compared with TBI. In CML in first chronic phase, Cy in combination with i.v. Bu was associated with less relapse than TBI or oral Bu. LFS was better after i.v. or oral Bu compared with TBI.

Allogeneic Stem Cell Transplantation for CML in Accelerate or Blastic Phase

Patients with advanced chronic myeloid leukemia (CML) in accelerate (AC) or blastic phase (BC) have a dismal prognosis despite the use of tyrosine kinase inhibitors (TKI). Here we report our experience for allogeneic stem cell transplantation (ASCT) in advanced and phase of CML. Between July 1990 and May 2012 88 patients with a median age of 36 years (range 7-76) received allogeneic stem cell transplantation from related (n=34) or unrelated (n=54) donors , including 19 HLA-mismatched donors after myeloablative (n=54) or reduced intensity (n= 34) conditioning. Stem cell source was bone marrow (n=37) or peripheral blood stem cells (n=51). GvHD prophylaxis consisted of calcineurin inhibitor plus short course MTX or MMF. Most of the patient received additional ATG as GvHD prophylaxis (84%).The majority of patient (75%) received TKIs before ASCT. 50% received one TKI, 8 received 2 TKIs and 2 received 3 TKI before ASCT. At time of transplantation 34 patient achieved a second or subsequent chronic phase, 28 were in accelerate and 25 in blastic phase. Overall the median number of blasts at time of ASCT was 18.75% (range 5-58%) and the time from diagnosis to transplantation was 27 months (range 3-296).No primary graft failure was observed. The incidence of acute graft versus host disease (GvHD) grade II to IV was 43% and of severe grade III/IV GvHD was 28%. Forty-two percent of the patient experienced chronic GvHD.The non-relapse mortality (NRM) at 1 and 5 years was 22% (95% CI; 14-30%) and 23% (95%CI: 13-33%), respectively. In a multivariate analysis (MVA) only higher number of transplanted CD34+ cells were associated with a lower risk of NRM (HR 0.850, 95%CI: 0.729-0.992, p=0.04). The cumulative incidence of relapse at 5 years was 43% (95% CI: 31-55%). In a MVA age > 40 years (HR 2.272, 95%CI: 1.112-4.645, p=0.024) and Reduced intensity conditioning (HR 2.034, 95%CI: 0.998-4.144, p=0.051) were significant factors for higher risk of relapse. After a median follow-up of 91 months (r., 52-133) the estimated 5 and 10 year overall survival was 44% (95% CI: 32-56) and 40% (95% CI: 28-52%), respectively. In an univariate analysis overall survival was significantly influenced by stem cell source, gender, CD34 transplanted cell number and blastic phase at time of transplantation. However, the only significant factor for improved survival in a MVA was a higher number of transplanted CD34+ cells (HR 0.916, 95%CI: 0.844-0.916, p=0.038). DisclosuresNo relevant conflicts of interest to declare.

Early administration of donor lymphocyte infusions upon molecular relapse after allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia: a study by the Chronic Malignancies Working Party of the EBMT.

Patients with chronic myeloid leukemia relapsing after allogeneic hematopoietic stem cell transplantation may be treated by tyrosine kinase inhibitors and/or by donor lymphocyte infusions. The best strategies and timing of administration of lymphocytes are unclear. We analyzed 155 patients who relapsed after allogeneic stem cell transplantation with disease detectable only by molecular methods and who subsequently received lymphocytes. Transplants were performed in first chronic phase (n=125) or in advanced disease (n=29) from identical siblings (n=84) or unrelated donors (n=71) between 1986 and 2003. They received lymphocytes either during molecular relapse (n=85) or upon progression to more advanced disease (1993 to 2004). The median interval from relapse to lymphocyte infusion was 210 (0-1673) days. The median follow up after it was 46 (3-135) months. Overall survival was 76±4% at five years after lymphocyte infusions (89±8% with sibling donors and 63±13% with unrelated donors (P=0.003)). Survival was 69±14% when lymphocytes were given within six months of the detection of molecular relapse and 81±10% (P=0.061) when given later; 81±11% if given at molecular relapse versus 71±12% (P=0.26) with more advanced disease. In multivariate analysis survival was worse if the donor was unrelated (HR 2.54 (95% CI: 1.15-5.53), P=0.021) and better with lymphocyte infusions beyond six months from molecular relapse (HR 0.4 (95%CI: 0.19-0.84), P=0.018). These data confirm the remarkable efficacy of lymphocyte infusions for this disease. There appears to be no advantage from administering it early upon detection of molecular relapse in patients who received allogeneic stem cell transplantation for chronic myeloid leukemia.