Clinical Study of Allo-HSCT with Conditioning Regimen Containing Decitabine in the Treatment of advanced Acute Myloid Leukemia and Myelodysplastic Syndrom

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment options to hematologic malignancies. However, majority of patients with refractory or resistant hematologic malignancies can not achieve remission before transplantation. And the relapse rate of these patients after transplantation remains high obviously. Therefore, it is necessary to design a safe and effective conditioning regimen to improve the remission rate of these patients and disease-free survival (DFS), but to reduce transplantation related mortality (TRM). The optimal conditioning regimen not only can reduce tumor burden and eradicate minimal residual disease but also can make immunosuppressive state to ensure engraftment. As well as, it does not increase the TRM. One of the promising drugs of epigenetics is decitabine (DAC), which has a significant effect on a variety of hematologic malignancies. It is widely used in myelodysplastic syndromes(MDS) even for relapsed and refractory acute myelocytic leukaemia (AML). Because decitabine can not only up-modulate the tumor-associated antigen express on surface of leukemia cells to increase graft-versus-leukemia (GVL) effect but also can reduce the incidence of graft-versus-host disease (GVHD) by increase the number of regulatory T Cells（Tregs）. Aims: This clinical study will investigate the security and efficacy of conditioning regimen containing decitabine. Further to explore the role in advanced malignant hematologic disease. Methods: We retrospectively studied 20 cases of patients with hematologic malignancies, who underwent allo-HSCT with decitabine combined with conditioning regimens in the Department of Hematology, the First Affiliated Hospital of Soochow University during May 1, 2012 to April 30, 2014. Results: 19 patients achieved complete remission and hematopoietic reconstitution after transplantation. Only 1 NR case died on day +27 post transplant. The median time of neutrophil and platelet reconstitution were 12 (10-22) and 14.5 (12-35) days respectively. The median time of archiving full donor chimerism [short tandem repeat (STR)STR>95%] was 18(13-62) days. The median follow-up post transplant was 246 (19-582) days. 3 cases relapsed. 2 cases were dead due to relapse.1 case achieved complete remission again after donor lymphocyte infusion (DLI). 1 CR case was dead due to hemorrhage of digestive tract. The other 15 CR cases were survival with continued remission. The estimated 2-year overall survival (2yr-OS) rate was 78%.The 2 year disease-free survival (2yr-DFS) rate was 62.6%. The cumulative relapse rate was 26.7%. The transplantation-related mortality (TRM) rate was 0. Furthermore, the estimated 2-yr OS and DFS of patients with DNMT3A mutations or abnormalities of chromosome 7 and complex chromosomal karyotype were 72.9% and 60.6% respectively. Concerning about transplant related toxicity, except one case has grade III gastrointestinal toxicity, all the other toxicities were mild (grade I-II). The cumulative rate of aGVHD and cGVHD were 20.5% and 48.3%.And the cumulative rate of aGVHD for grade I-II and grade II-IV were 15% and 10.5%. Conclusions Allo-HSCT is an effective treatment for refractory and relapsed AML and high- risk MDS. It is feasible to use conditioning regimen containing decitabine before allo-HSCT. The treatment were well tolerated. 92.3% of the patiants achieved CR, and were well engraftment. Because of decitabine can promote megakaryocytic maturation and accelerate the release of platelet, so hematopoietic was reconstructed rapidly, especially for the megakaryocyte. The 2yr-DFS rate was 62.6%, the cumulative relapse rate was 26.7%. The conditioning regimen containing decitabine before allo-HSCT seems to reduce the incidence of aGVHD. The prognosis and survival of the patients with complex chromosomal karyotype or chromosome 7 abnormalities or DNMT3A mutation may be improved by treating with decitabine containing conditioning regimen. Disclosures No relevant conflicts of interest to declare.

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Low-Dose Decitabine Combined with Modified Bucy Is More Effective Conditioning Regimen for High-Risk Patients with Acute Myeloid Leukaemia/Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v128.22.5750.5750 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5750-5750

Author(s):

Xiaowen Tang ◽

Jing Cao ◽

Xiaojing Shi ◽

Ling Ge ◽

Aining Sun ◽

...

Keyword(s):

High Risk ◽

Low Dose ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Hematologic Malignancies ◽

Advanced Stage ◽

Free Survival ◽

Risk Patients ◽

Disease Free ◽

Related Mortality

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment options to hematologic malignancies. However, majority of patients with refractory or resistant AML/MDS can not achieve remission before transplantation. It is necessary to design a safe and effective conditioning regimen to reduce tumour burden, improve remission rates, decrease transplantation-related mortality, and improve disease-free survival (DFS) in patients with advanced acute myloid leukemia(AML) and myelodysplastic syndrom(MDS). One of the promising drugs of epigenetics is decitabine (DAC), which has a significant effect on a variety of hematologic malignancies including MDS and advanced AML. Furthermore, decitabine can not only up-modulate the tumor-associated antigen express on surface of leukemia cells to increase graft-versus-leukemia (GVL) effect but also can reduce the incidence of graft-versus-host disease (GVHD) by increase the number of regulatory T Cells (Tregs). Objective: To investigate the security and efficacy of conditioning regimen containing low-dose decitabine combined with modified BUCY regimen for advanced AML/MDS patients, explore the role of immunomodulatory activity post transplantation and compared this regimen with conventional modified BUCY regimen. Methods: Between January 2012 and March 2015, a total of 156 patients were enrolled in this retrospective study. In which, there were 46 patients who received a conditioning regimen of low-dose DAC and a modified BUCY regimen(DAC group) followed by allo-HSCT, and the second cohort consisted of 110 who only received a conventional modified BUCY regimen(Con group). Comparing the baseline of two groups, there were no significant difference except there were more advanced stage patients in DAC group(63% vs 32.7%,p=0.007). A modified BUCY conditioning regimen include semustine (250 mg/m2/d) for 1 d(-10d), cytarabine (2 g/m2 q12 h) for 2 d (-9 d to -8 d), busulfan (0.8 mg/kg/6 h) for 3 d (-7 d to -5 d), and cyclophosphamide (1.8 g/m2/d) for 2 d (-4 d to -3 d). Meanwhile, patients in the DAC group received the DAC treatment for 3 to 4 d with a total of 100 mg/m2 before modified BUCY regimen. Results: In DAC group, all patients engrafted successfully, including 29/46(63%) non-remission (NR) patients. However, there were seven patients presented graft failure in Con group. The transplantation-related mortality (TRM) rate was significantly lower in DAC group(0% vs 13.6%, p=0.019). The median time of neutrophil recovery was 12(10-21)d vs 12(10-23)d, and platelet recovery was 13(10-35)d vs 14(9-40)d, respectively in DAC and Con group, and there were no significant differences. With the median follow-up of 277.5(39-985)d and 221(3-1237)d in two groups, the cumulative relapse rate(RR) was 38.2% vs 36.8% (p=0.951). The incidence rate of aGVHD was lower in DAC group(26.7% vs 46.8%, p=0.034), while there were no diference in the incidence rate of cGVHD(68.4% vs 70.7%, p=0.598). Compared with Con group, the estimated 2-year overall survival (2yr-OS) rate and 2 year disease-free survival (2yr-DFS) rate were both higher in DAC group(2yr-OS:45.6% vs 75.3%, p=0.007, Fig 1; 2yr-DFS:39.1% vs 51.5%, p=0.076). Furtheremore, for patients in advanced stage before transplant, the estimated 2yr-OS was 37.2% vs 72.7%(p=0.009) and 2yr-DFS rate was 38.5% vs 49.8%(p=0.051), respectively. For AMLs, the estimated 2yr-OS rate in DAC and Con group was 75.0% vs 43.0%(p=0.034), and for advanced stage AMLs, the estimated 2yr-OS rate was 66.1% vs 29.7%( p=0.031). Regarding the early relapse rate(RR) of 6 months post transplant, DAC group were less than that of Con group(11.5% vs 35.3%, p=0.124). Conclusion: 1. Low-dose decitabine combined with modified BUCY is a safe and effective conditioning regimen for high-risk patients with AML/MDS with low toxicity and well tolerance. 2. 100% NR patients of DAC group achieved complete remission with full donor chimerism at d30. 3.Comparing with Con group, patients in DAC group had ralative lower incidence of aGVHD, TRM and RR but relative higher estimated 2-yr OS and DFS, especially for advanced stage patients. Disclosures No relevant conflicts of interest to declare.

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Allogeneic and Matched Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT) for Hematologic Malignancies Using a Modified Reduced Intensity Conditioning Regimen.

Blood ◽

10.1182/blood.v106.11.5324.5324 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5324-5324

Author(s):

Marion Raflores ◽

James Rossetti ◽

John Lister ◽

Richard Shadduck ◽

John Lech ◽

...

Keyword(s):

Stem Cell ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Free Survival ◽

Reduced Intensity Conditioning Regimen ◽

Disease Free ◽

Related Mortality

Abstract INTRODUCTION:Use of a reduced intensity conditioning regimen (RICR) in hematopoietic stem cell transplant may result in lower treatment related mortality (TRM), less acute graft versus host disease (aGVHD) and better survivability, utilizing the graft versus tumor effect from HSCT. METHODS: Our institution’s original RICR protocol conditioning regimen (Trial A) consists of fludarabine 30 mg/m2 (Day-5 to D-2), melphalan 140–180 mg/m2 (Day -3) and ethyol 910 mg/m2 (Day-3) in addition to mycophenolate mofetil 1 g q12H and tacrolimus(serum level 5–15 ng/ml) beginning Day -3 as immunosuppressive therapy. Transplantation was done using peripheral blood stem cells from the best HLA-antigen match sibling (allo) or matched unrelated donor (MUD). We retrospectively compared transplant data from this original protocol to a modified RICR protocol (Trial B) using a lower dose of melphalan 100mg/m2 and addition of thymoglobulin 2mg/kg/d (D-2 to D0). RESULTS: 46 patients were transplanted in Trial A with median age of 46 years. 25 patients had allogeneic and 21 had MUD transplant. 30 patients were transplanted in Trial B with median age of 44 years. 22 patients had an allogeneic and 8 had a MUD transplant. All patients were heavily pretreated with 13 patients in Trial A and 9 patients in Trial B have undergone at least one previous stem cell transplant. At D30, all patients in Trial B were alive while 11% of patients in Trial A died of treatment related cause. At D100, 51% of patients in Trial A and 70% of patients in Trial B were alive. D100 TRM was 40% in Trial A and 20% in Trial B. Table 1. Treatment Outcome OS(%) TRM (%) RM (%) Trial A Trial B Trial A Trial B Trial A Trial B OS:overall survival TRM:treatment related mortality RM: relapse mortality 30 Days MUD 81 100 19 0 0 0 Allo 96 100 4 0 0 0 Total 89 100 11 0 0 0 100 days MUD 40 63 60 38 0 0 Allo 60 73 24 14 16 14 Total 51 70 40 20 9 10 1 year overall survival was 30% in trial A and 20% in Trial B. 1 year disease free survival (DFS) was 18% in trial A and 13% in Trial B. Table 2. 1 year treatment outcome* Overall Survival(%) Disease Free Survival (DFS) % Trial A Trial B Trial A Trial B *for Trial B, 5 living patients have not yet reached 1 year follow-up MUD 21 13 14 0 Allo 37 23 21 18 Total 30 20 18 13 Incidence of aGVHD≥2 in patients not receiving DLI and alive for more than 30 days post transplant was 56% in Trial A (MUD 67%, Allo50%) and 25% in Trial B (MUD63%, Allo 6%). At D100, aGVHD was the most common cause of death in Trial A while overwhelming sepsis was leading cause of death in Trial B. WBC engraftment with ANC>500 was achieved in 98% of patients in Trial A and 93% of patients in Trial B. Average day of engraftment was 13 days in Trial A and 15 days in Trial B. Platelet engraftment with platelet count at least 20,000 was achieved in 80% of patients in both protocols with average day of engraftment at 18 days in Trial A and 21 days in Trial B. 95% of patients in Trial A had achieved at least 80% donor marrow cells at D100 while only 81% achieved this level of chimerism in Trial B. CONCLUSION: The modified RICR protocol for HSCT is a tolerable regimen which results in a lower incidence of D100 TRM and aGVHD but overall and disease free survival are not improved. Marrow engraftment is achieved although slightly delayed compared to the original protocol.

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Busulfan/etoposide--initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia

Blood ◽

10.1182/blood.v81.2.319.319 ◽

1993 ◽

Vol 81 (2) ◽

pp. 319-323 ◽

Cited By ~ 47

Author(s):

NJ Chao ◽

AS Stein ◽

GD Long ◽

RS Negrin ◽

MD Amylon ◽

...

Keyword(s):

Bone Marrow ◽

Complete Remission ◽

Median Time ◽

Relapse Rate ◽

Disease Free Survival ◽

Autologous Bone Marrow ◽

Free Survival ◽

Acute Nonlymphoblastic Leukemia ◽

Disease Free

Abstract Current intensive chemotherapy for acute nonlymphoblastic leukemia (ANLL) results in a complete remission in the majority of patients. Unfortunately, the duration of remission is short and most of the patients will experience a relapse of their underlying disease. Autologous bone marrow (BM) transplantation is being explored as a treatment modality designed to improve relapse-free survival. We have conducted a phase II trial exploring the combination of busulfan (16 mg/kg) and etoposide (60 mg/kg) in an attempt to improve antitumor efficacy using this novel preparative regimen. To date, 50 patients (48 with ANLL and 2 patients with biphenotypic acute leukemia) have been treated. The first 20 patients received unmanipulated BM; 28 patients subsequently received 4-hydroperoxycyclophosphamide (4–HC) (60 micrograms/mL)-purged bone marrow, and 2 patients with biphenotypic acute leukemia received both 4–HC (60 micrograms/mL) and etoposide (5 micrograms/mL)-purged BM. Thirty-four patients were in first complete remission (CR1), 12 patients in second complete remission (CR2), and 4 patients in relapse. The median time from first complete remission to BM harvest was 3 months (range, 0.8 to 4) compared with median time of 2 months (range, 1.5 to 5.0) for patients in second complete remission. The median time from harvest to transplant was 1 month for both groups (range, 0.4 to 36). A median of 0.7 x 10(8) (range, 0.2 to 1.4) mononuclear cells were infused. Patients achieved an absolute neutrophil count of > or = 500/microL at a median of 26 days (range, 13 to 96), an untransfused platelet count > or = 20,000/microL at a median of 56 days (range, 15 to 278) and a sustained hematocrit > or = 30% at a median of 50 days (range, 19 to 116). Twenty-six patients are alive and in continued CR. Follow-up of the surviving patients ranged from 6 months to 66 months with a median follow-up of 31 months. Patients receiving purged BM have an actuarial disease-free survival of 57% with a relapse rate of 28% compared with patients receiving unpurged BM whose actuarial disease-free survival is 32% with a relapse rate of 62% (P = .06 for relapse rate). The most significant extramedullary toxicities for this regimen are hepatic and cutaneous (including mucositis). The BU/VP-16 regimen is associated with a significant proportion of patients surviving disease free, especially in the group receiving purged BM. Whether this regimen offers a substantial improvement in disease-free survival over currently used regimens will require a prospective randomized study.

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Improved Outcomes for Peripheral Blood Stem Cell Transplantation in Advanced Myelodysplastic Syndrome.

Blood ◽

10.1182/blood.v104.11.2304.2304 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2304-2304

Author(s):

Scott R. Solomon ◽

Richard Childs ◽

Aldemar Montero ◽

Elaine Sloand ◽

Laura Wisch ◽

...

Keyword(s):

Stem Cell ◽

Peripheral Blood Stem Cell ◽

Advanced Disease ◽

Disease Free Survival ◽

Free Survival ◽

Disease Free ◽

Blood Stem Cell Transplantation ◽

Reduced Intensity ◽

Risk Of Relapse ◽

Related Mortality

Abstract Allogeneic marrow or peripheral blood stem cell transplantation (PBSCT) is the only curative treatment for myelodysplastic syndrome (MDS). Historically, transplantation for MDS has produced long-term disease-free survival rates of 30–40%, partially due to high procedural mortality (~40%) in this patient population. Although transplant outcomes in younger patients with low-risk disease have been favorable, inferior results are seen in older patients and those with more advanced disease. Evidence suggests that the lower transplant-related mortality (TRM) and improved graft-versus-leukemia seen with PBSCT may translate into improved clinical outcomes for MDS patients. Forty-four patients, aged 12–73 years (median 50) received a PBSCT from a matched related sibling donor (MRD). Patients aged <55 years, without prohibitive comorbidity, received myeloablative conditioning consisting of total body irradiation and cyclophosphamide, followed by a T cell depleted allograft and scheduled post-transplant donor lymphocyte infusions (MST, n=23). Patients ineligible for an ablative transplant due to age or poor health received reduced intensity conditioning (fludarabine and cyclophosphamide, melphalan, or busulfan) followed by a T cell replete allograft (n=21). Six patients had low-risk MDS (RA/RARS), while the majority of patients (86%) had advanced disease (RAEB [9], RAEBT [6], AML [13], therapy-related MDS [10]). Median follow-up is 15.3 (range 2–82) months. Patients with therapy-related MDS had a significantly lower survival rate due to a very high risk of relapse (figure). The actuarial probabilities of overall survival (OS), disease-free survival (DFS), relapse, and TRM were 64%, 59%, 26%, and 23% for primary MDS patients, and 51%, 47%, 40%, and 25% for the whole cohort. Transplant-related mortality in patients under 50 years of age was 11% vs. 45% in patients ≥50 years (p=0.03). OS and DFS were significantly better in recipients of MST (64%, 57%) than in patients receiving reduced-intensity PBSCT (33%, 34%), due to a higher risk of relapse in the latter group (55% vs. 29%, p=0.10). In nineteen patients <50 years receiving MST, actuarial probability of OS, DFS, relapse, and TRM were 81%, 72%, 23%, and 7%, respectively. In summary, PBSCT yields superior outcomes for patients with primary MDS, even in patients in transformation to AML. The inferior outcomes seen in therapy-related MDS suggest alternative therapies are required for this patient population. Reduced intensity transplantation permits curative therapy for MDS patients not amenable to MST, but at the price of increased TRM and relapse in this older cohort. Figure Figure

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Chronic Graft Versus Host Disease and Pretransplant Disease Status Predict Outcomes in Patients with Hematologic Malignancies Undergoing Reduced Intensity Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v110.11.5090.5090 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5090-5090

Author(s):

Megha A. Shah ◽

Mounzer Agha ◽

Markus Mapara ◽

Kate Lenhart ◽

Anastasios Raptis

Keyword(s):

Overall Survival ◽

Median Overall Survival ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Disease Status ◽

Hematologic Malignancies ◽

Free Survival ◽

Effective Treatment Modality ◽

Disease Free ◽

Reduced Intensity

Abstract Reduced intensity stem cell transplantation (SCT) is an effective treatment modality for patients with hematologic malignancies who are not candidates for conventional myeloablative SCT. We conducted a retrospective review of all patients with hematologic malignancies receiving a reduced intensity allogeneic SCT from July 2002 to July 2007. Data pertaining to patient demographics, engraftment, disease status pre and post transplant, graft versus host disease (GVHD), and HLA matching was analyzed to identify factors significantly affecting the clinical outcome. Seventy three patients, with a median age of 55 (range of 19–70) and with the diagnoses of ALL (n=8), AML (n=30), CLL (n=3), CML (n=1), Hodgkin’s (n=7), non-Hodgkin’s (n=7), MDS (n=11), and MM (n=6) underwent a reduced intensity SCT using a fludarabine based conditioning regimen. Thirty nine (53%) received unrelated donor grafts and 34 (47%) received sibling donor grafts. Fifty six patients (77%) received fully matched grafts whereas 17 patients (23%) had an antigen or allele mismatch. Acute GVHD grade II-IV was observed in 27 of the 73 patients and chronic GVHD was seen in 18 of the 48 patients who could be evaluated. Seventeen patients developed transplant related fatal complications and 30 patients died from disease progression or relapse. Median time to neutrophil recovery was 15 days (range of 9–41 days) and median time to platelet recovery was 18 days (range of 9–42 days). Graft failure was observed in 6 of the 73 patients. Median overall survival and disease free survival for all patients was 7.7 and 6.6 months respectively. Median overall survival for patients with persistent disease or in remission at the time of the SCT was 5.6 and 21.8 months (p= 0.01) while that for disease free survival was 5.7 and 8.4 months (p=0.06). Median overall survival with and without chronic GVHD was 25.6 and 9.4 months (p <0.0001) while median disease free survival was 18.2 and 6.0 months (p< 0.0001). Patients with limited chronic GVHD have not yet reached median overall survival while the median disease free survival was 18.4 months. Those with no or extensive chronic GVHD had medians of 9.4 and 9.2 months for overall survival and 6.0 and 9.2 months for disease free survival (p= 0.004 and p=0.02). The source of the stem cells as well as the administration of allele or single antigen mismatch grafts did not affect the outcome. Reduced intensity SCT is an effective treatment modality in patients with hematologic malignancies, though it is most effective in patients who are in remission at the time of transplant and should be offered in this setting. Patients with limited chronic GVHD had a better outcome suggesting the presence of potent anti-tumor activity of the donor immune competent cells without the detrimental effects in clinical outcome caused by extensive chronic GVHD.

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One Antigen HLA-Mismatched Related and 8/8 Allele Matched Unrelated Donors Are Associated with Similar Survival after Hematopoietic Cell Transplantation for Acute Leukemia.

Blood ◽

10.1182/blood.v112.11.965.965 ◽

2008 ◽

Vol 112 (11) ◽

pp. 965-965

Author(s):

David Valcarcel ◽

Fangyu Kan ◽

Tao Wang ◽

Stephanie J. Lee ◽

Stephen R Spellman ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Unrelated Donors ◽

Related Donor ◽

Disease Free

Abstract Patients in need of an allogenetic hematopoietic cell transplant but who lack an HLA genotypically identical sibling donor, are faced with the decision to consider a single HLA antigen mismatched related donor, or a search for a suitable 8/8 matched unrelated donor. We compared the outcomes of adult patients (≥18 years old) receiving a transplant for the treatment of AML or ALL in first or second remission from either a one-antigen mismatched related donor (MMRD group, N=89) reported to the CIBMTR or an 8/8 HLA-A, B, C and DRB1 allele matched unrelated donor (UD group, N=700) facilitated by the NMDP between 1995–2005. MMRD group was typed by serological or DNA-based methods for HLA-A, -B and –DR with all results verified by lab report review. The UD group was retrospectively typed for HLA-A, B, C and DRB1 by high resolution typing methods. Most received myeloablative conditioning regimens (77%), calcineurin inhibitor-based GVHD prophylaxis (100%) and T cell replete grafts (100%). 13% received ATG with the conditioning regimen. Median follow-up was 54 and 38 months in the MMRD and UD groups, respectively. The MMRD group was younger (median age 35 vs 43, p=0.002), had more ALL patients with low-risk cytogenetics (43% vs 18%, p=0.005), had older donors (median age: 38 vs 34, p=0.047), were more likely to receive methotrexate for GVHD prophylaxis (89% vs 77%, p=0.014) and were more likely to be transplanted prior to 2001 (62% vs 24%; p<0.001). There were no differences in patient or donor gender, diagnosis, disease-status, cytogenetic-risk of AML, time from diagnosis to transplant, stem cell source, conditioning regimen, use of ATG and Karnofsky index. Univariate comparisons (MMRD vs. UD) showed: 3-year OS (42% vs 44%, p=0.647), 3-year DFS (41% vs 41%, p=0.931), 3-year TRM (39% vs 31%, p=0.136), 3-year incidence of relapse (20% vs 28%, p=0.094), grade III–IV acute GVHD by 100 days (22% vs. 15%, p=0.147), chronic GVHD by 1 year (35% vs 47%, p=0.029). All multivariate analyses were adjusted for patient and transplant characteristics and are shown in the table below. In summary, transplants utilizing one-antigen mismatched related and 8/8 allele-matched unrelated donors did not significantly differ in overall survival or disease free survival, but chronic GVHD was more frequent after UD transplantation. Outcome RR (MMRD vs. UD) 95% CI p-value Survival 0.99 0.73–1.34 0.94 Disease-free survival 1.06 0.80–1.41 0.69 Treatment related mortality 1.14 0.77–1.69 0.52 Relapse 0.81 0.50–1.30 0.38 Acute GVHD III–IV 1.53 0.91–2.57 0.11 Chronic GVHD 0.58 0.39–0.85 0.006

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The Role of Hematopoietic Cell Transplantation (HCT) for Burkitt Lymphoma: a Report From the Center for International Blood and Marrow Transplant Research (CIBMTR)

Blood ◽

10.1182/blood.v116.21.2390.2390 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2390-2390

Author(s):

James L. Gajewski ◽

Jeanette Carreras ◽

Hillard M. Lazarus ◽

Ginna G. Laport ◽

Silvia Montoto ◽

...

Keyword(s):

Burkitt Lymphoma ◽

Conflicts Of Interest ◽

Conditioning Regimen ◽

Disease Free Survival ◽

B Cell Lymphoma ◽

Unrelated Donor ◽

Free Survival ◽

Disease Free

Abstract Abstract 2390 Burkitt lymphoma (BL) is an aggressive B cell lymphoma primarily affecting children and young adults and is characterized by the highest doubling time of any tumor. Cyclical intensive chemotherapy and rituximab confer high complete remission (CR) rates and 80% long term disease free survival in chemotherapy sensitive disease. The role of autologous (autoHCT) or allogeneic (alloHCT) transplant is not well described in BL. We report the outcomes of 241 recipients of HCT for BL between 1985 and 2007 reported to the CIBMTR. Five patients (pts) received syngeneic twin grafts in addition to autoHCT in 113 pts, HLA identical sibling alloHCT (SIB) in 80 pts and mismatched related or unrelated donor (UNR/MM) alloHCT in 48 pts. Baseline patient and disease related risk factors varied significantly between cohorts (table1). The autoHCT cohort had a higher proportion of pts with chemotherapy sensitive disease (86%), peripheral blood grafts (73%) and HCT in first CR (42%). In the UNR/MM cohort, 25% pts were chemotherapy resistant and only 6% were in CR1. The use of autoHCT has declined in recent years with the majority (81%) performed before 2001. Conditioning regimen for alloHCT was myeloablative in 88% (86% and 92% in SIB and UNR/MM respectively). Treatment related mortality (TRM) was higher in alloHCT recipients (table1). Cumulative incidence of relapse/progression at 5 yrs (95% CI) was 44 (35-53)% for autoHCT, 42(31-53)% for SIB and 48 (34-62)% for UNR/MM. For autoHCT, 5-yr progression free survival (PFS) was 48(39-58)%, 78% for those in first CR versus 27% for disease beyond CR1 (p<0.001). For alloHCT, 5-yr PFS was 50% for those in first CR versus 19% for disease beyond CR1 (p=0.001) (figure 1). 5-yr PFS was 30 (20-41)% for SIB and 22 (12-35)% for UNR/MM. Progressive BL was the commonest cause of death. Conclusion: While autoHCT and alloHCT are both feasible in patients with BL, the use of autoHCT appears to be declining in recent years concomitant with the advent of modern chemotherapy. AlloHCT was performed in those with considerably higher risk disease. Approximately one fifth of advanced BL pts receiving alloHCT beyond CR1 had long term disease free survival. Disclosures: No relevant conflicts of interest to declare.

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Genetic Variability In the Transcriptional Factor EP300 Strongly Influences the Clinical Outcome of Allogeneic Stem Cell Transplantation (Allo-SCT)

Blood ◽

10.1182/blood.v116.21.527.527 ◽

2010 ◽

Vol 116 (21) ◽

pp. 527-527

Author(s):

Beatriz Martin-Antonio ◽

Rocio Cardesa ◽

Isabel Álvarez ◽

Francisco Márquez-Malaver ◽

Alicia Báez ◽

...

Keyword(s):

Cell Proliferation ◽

Innate Immunity ◽

Clinical Outcome ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Genetic Characteristics ◽

Free Survival ◽

Advanced Phase ◽

Reduced Intensity Conditioning Regimen ◽

Disease Free

Abstract Abstract 527 Despite considerable progress in the management of infections, in more stringent criteria for HLA compatibility, in the use of new immunosuppressive drugs and in tailored conditioning regimens, allo-SCT is still associated with a considerable morbidity and mortality, especially due to infection and leukemic relapse. Little is known about the relative importance of genetic characteristics that influence individual responses to infection and to malignant cells. We hypothesized that individual non-HLA genetic characteristics of the donor and/or recipient may influence the degree of inflammatory and antileukemic responses after allo-SCT. The objective of this study was to examine – in both the donor and the recipient – single nucleotide polymorphisms (SNPs) in genes involved in innate immunity (HAMP, IRF-3, PTX3, HBD1, TGFB1) and in transcriptional factors (TF) (ATBF1 and EP300) and to evaluate their influence on clinical outcomes after allo-SCT, specifically on the incidence of disease free survival (DFS), overall survival (OS), transplant-related mortality (TRM), and relapse. The study was performed in a first cohort of 106 donor-patient pairs (Hospital Virgen del Rocío, Seville) and was later validated in a second cohort of 99 donor-patient pairs (Hospital Clinic, Barcelona). In the first cohort, patient median age was 38 years (range, 5–66); 52% were in advanced phase of disease; and 29% received a reduced intensity conditioning regimen. Although several SNPs were associated with clinical outcome in this cohort, the strongest association was found with the transcriptional factor EP300. The dominant variant AA in rs7193297 in EP300 codes for a missense change. Patients with this variant attained a higher DFS (44% vs 37%, p=0.01; OR=2, p=0.03) and OS (54% vs 25%, p=0.009; OR=2, p=0.03) and showed a trend towards a lower TRM (16% vs 31%, p=0.1; OR=2, p=0.1). In the second cohort, median age was 45 years (range, 17–64); 55% were in advanced phase of disease; and 23% received a reduced intensity conditioning regimen. Results in this group of patients were very similar to those found in the first cohort. Patients with the dominant variant in EP300 attained a higher DFS (53% vs 24%, p=0.018; OR=2, p=0.03) and OS (65% vs 34%, p=0.016; OR=2, p=0.03) and showed a trend towards a lower TRM (21 vs 32%, p=0.3). When both cohorts were analyzed together, differences between patients with the dominant variant and those with the recessive variant were more significant. Those with the dominant variant had a higher DFS (53% vs 24%, p<0.0001; OR=2, p=0.004) and OS (54% vs 34%, p=0.001; OR=2, p=0.005) and showed a trend towards a lower TRM (18% vs 31%, p=0.07; OR=1.7, p=0.09) and a lower relapse rate (31% vs 45%, p=0.04; OR=1.6, p=0.05). When the analysis was performed according to the presence of the SNP in donor and/or in patient, the association of EP300 with clinical outcome was stronger when the variant was present in both donor and recipient (figureA). EP300 is a histone acetiltranspherase that regulates transcription via chromatin remodelling; it is involved in viral infection by interacting with IRF3 to activate interferon transcription and plays an important role in hemopoietic stem cell proliferation and differentiation. Due to the importance of EP300 in the regulation of mRNA expression of innate immunity and cell proliferation genes, we analyzed rs7193297 in EP300 by real-time RT-PCR in healthy individuals. The dominant variant was associated with higher expression of innate immune genes (IRF-3, p=0.02; MIF, p=0.006), cell cycle genes (AURKB, p=0.01; CCNA2, p=0.005; CCNB1, p=0.02) and osmotic stress genes (NFAT5, p=0.03; SLC38A2, p=0.03) (figureB). Our findings indicate a beneficial effect for the dominant variant in EP300 on clinical outcome after allo-SCT, which might be explained by its influence in the mRNA expression of innate immunity and cell proliferation genes. Actuarial probability of disease-free survival according to the presence (+) or absence (-) of the dominant variant in rs7193297 in EP300 in donor (D) or in patient (P). B. Real-time RT-PCR in healthy individuals carrying the dominant genotype (AA) in rs7193297 in EP300 compared to individuals carrying the recessive genotype (GG). Disclosures: No relevant conflicts of interest to declare.

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Unmanipulated Haploidentical Bone Marrow Transplantation and Post-Transplant Cyclophosphamide for Hematologic Malignanices Following A Myeloablative Conditioning.

Blood ◽

10.1182/blood.v120.21.3034.3034 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3034-3034

Author(s):

Andrea P Bacigalupo ◽

Anna Maria Raiola ◽

Alida Dominietto ◽

Maria Teresa Van Lint ◽

Francesca Gualandi ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Myeloablative Conditioning ◽

Free Survival ◽

Disease Free ◽

Active Disease ◽

Related Mortality

Abstract Abstract 3034 Despite a large number of unrelated donors (UD), not more than 30% of patients who have activated a donor search, undergo an allogeneic UD stem cell transplant. HLA haploidentical family members are being increasingly considered as an alternative donors, both using T cell depleted or T cell replete grafts. Post-transplant high dose cyclophosphamide (PT-CY), introduced by the Baltimore group, has shown very promising results following non myeloablative conditioning regimens. We are now reporting 50 patients with high risk hematologic malignancies, who received a myeloablative regimen, followed by unmanipulated haploidentical bone marrow transplant (hBMT) and PT-CY. The myeloablative conditioning consisted of thiotepa (10 mg/kg), busulfan (9,6 mg/m2̂), fludarabine (150 mg/m2̂)(n=35), or total body irradiation (9,9–12 Gy), fludarabine (120 mg/m2̂) (n=15). The median age was 42 years (18–66); 23 patients were in remission and 27 had active disease; 10 patients were receiving a second allograft. Graft versus host disease (GvHD) prophylaxis consisted in PT-CY on day+3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median nucleated cell dose was 3.6 ×108̂/kg (range: 1,4 – 7,7). The median time to neutrophil counts of >0.5×109/L was 18 days (range, 13–30 days) and to platelet counts of >20×109/L 23 days (range, 14 – 58 days), respectively. There was no correlation between infused number of nucleated cells and days of neutrophil engraftment. The cumulative incidence of engraftment was 90%for neutrophils and 86% for platelets. Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full donor chimerism on day +30. The cumulative incidence of grade II-III acute GvHD was 12%, and of moderate chronic GvHD 10%. With a median follow up for surviving patients of 333 days (149–623), the cumulative incidence of transplant related mortality is 18%, and the rate of relapse 26%. The actuarial 22 months disease free survival is 68% for patients in remission and 37% for patients with active disease (p<0.001). Causes of death were pneumonia (n=3), haemorrhage (n=3), sepsis (n=3) and relapse (n=7). In conclusion, a myeloablative conditioning regimen followed by h-BMT with PT-CY, results in a low risk of acute and chronic GvHD and encouraging rates of transplant related mortality and disease free survival. Disclosures: No relevant conflicts of interest to declare.

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Disease-Free Survival Of Myelodysplastic Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation Is Not Associated With Disease Status and Donor Sources

Blood ◽

10.1182/blood.v122.21.2158.2158 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2158-2158

Author(s):

Yue Lu ◽

Tong Wu ◽

Xing-Yu Cao ◽

Yan-Li Zhao ◽

De-Yan Liu ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Disease Free Survival ◽

Disease Status ◽

Refractory Anemia ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Free Survival ◽

Disease Free ◽

Related Mortality

Abstract Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is an only curative modality currently for myelodysplastic syndrome (MDS). High-risk MDS usually has lower complete remission (CR) rate and higher chemotherapy-related mortality compared with de novo acute myeloid leukemia (AML). To examine whether CR before HSCT has survival benefit for MDS treated by HSCT, we retrospectively analyzed the data during 11 years from our center. The clinical outcomes of MDS after HSCT from different donor sources have also been evaluated. Objective In present clinical study, the effects of disease status and donor sources on disease-free survival (DFS) of MDS after HSCT were studied. Methods From August 2001 to December 2012, total 122 patients with MDS that underwent HSCT in our center were enrolled. Male to Female was 76: 46. The median age was 35 (8 to 57) years old. The median blasts in bone marrow (BM) before conditioning were 9% (1% to 65%). According to 2008 WHO classification, the patients were diagnosed as refractory cytopenias with unilineage dysplasia (RCUD) in 12, refractory anemia with ring sideroblasts (RARS) in 2, 5q- in 1, refractory cytopenias with multilineage dysplasia (RCMD) in 15, refractory anemia with excess blasts (RAEB) -1/RAEB-2 in 36 and transformed AML in 56. For International Prognostic Scoring System (IPSS), 12 patients were in low-risk, 27 in intermediate-1, 24 in intermediate-2, and 59 in high-risk. Based on BM blast percentage pre-conditioning, 47 cases were less than 5%, 43 patients were between 5% to 20%, and 32 cases were more than 20%. The stem cells were from identical siblings (45) or unrelated donor (24) or haploidentical family members (53). Conditioning regimens were BUCY/BUFLU for identical sibling HSCT, and BUCY/BUFLU plus ATG (Thymoglobuline, 8-10mg/kg) for unrelated or haploidentical transplants. Graft-versus-host disease prophylaxis was employed by Cyclosporin A, Methotrexate and Mycophenolate mofetil as reported previously (DP Lu et al., Blood 2006; 107:3065). Results: With median follow-up 31 (1-144) months, DFS was 73.8%. Fourteen patients (11.4%) relapsed. Transplant-related mortality was 14.8%. No significant differences on DFS were found among RCUD/RARS/5q- (68.8%), RCMD (85.7%), RAEB-1/RAEB-2 (72.2%) and transformed AML (73.2%) (p=0.761). A similar DFS was seen in different risk categories (73.3% in low-risk, 79.2% in intermediate-1, 75.0% in intermediate-2 and 71.2% in high-risk; p=0.861). Moreover, CR or not before HSCT has no remarkable effect on DFS (blasts <5%, 78.7%; blasts 5% to 20%, 67.4%; blasts > 20%, 75.0%; p=0.342). Donor sources have also no significant effects on DFS (identical sibling 75.6%, unrelated donor 79.2%, haploidentical family member 69.8%; p=0.651). Conclusions Our clinical results have shown that under current protocol, DFS of MDS after allogeneic HSCT is quite encouraging no matter the disease status and stem cell donor sources. Therefore, it is not necessary that complete remission is achieved by chemotherapy before transplant. Haploidentical family member is an important alternative donor for patients with MDS when matched either identical sibling or unrelated donor is not available. Disclosures: No relevant conflicts of interest to declare.

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