bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Response to Tyrosine Kinase Inhibitors (TKIs) for Chronic Myeloid Leukemia (CML), the Experience At Tawam Hospital, Abudhabi, UAE
Authors: Alam Arif , Hussain Sabir , Lal Amar , Lee Donna , Kristensen Jorgen
Published: October 2019

Abstract 4458

Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a balanced reciprocal translocation involving the long arms of chromosomes 9 and 22. The fusion gene that is created by this translocation (BCR-ABL1) encodes for a constitutively active protein tyrosine kinase that is primarily responsible for the leukemic phenotype.

Targeted therapy with Tyrosine Kinase Inhibitors (TKIs) has become the recommended first-line treatment for patients with CML. Monitoring of the CML is done with quantification of the BCR-ABL transcripts by RQ-PCR–based molecular technique.

Twenty nine patients were diagnosed with CML in chronic phase between January 2009 till June 2012. The median age was 32 years (range 22–68 years). Male to female ratio was4.14:1. Three patients were lost from follow up after diagnosis and are excluded. Molecular response is available for 16 patients. Nine patients were treated with Imatinib 400 mg daily, four with Dasatinib 100 mg daily and three with Nilotinib 400 mg BID daily as upfront therapy. Twelve patients have achieved MMR/CMR (75 %) within 18months of starting therapy. Four patients have failed to achieve MMR by 24 months. All non responders were on Imatinib. Interestingly six (37.5%) patients achieved MMR/CMR within 9 months of starting TKIs. Of these only 1 was on Imatinib while the rest were on 2nd generation TKIs (Nilotinib 3 and Dasatinib 2).

MMR report from Enestnd trial is 67–71% in favor of Nilotinib as compared to Imatinib 44%, while the Dasision trial reported a MMR of 44 % in favor of Dasatinib with faster rate to response. Our results mirror the results of these phase 3 randomized trial with MMR/CMR of 75 %. Until today there has been no case of progressive disease.

Our data is limited but shows that the median age is much lower compared to Western countries, just reflecting differences in the age distribution of the population in the UAE with 80% being below the age of 65 years. Expatriates accounts for approximately 80% of the population in the UAE and many are temporary employed, having limited health care coverage, limited financial means as well as limited possibilities to attend regular follow-ups. This leads to compliance problems, loss from follow-up and suboptimal management and monitoring of their disease.

Disclosures:

Alam: BMS/Novartis: Consultancy, Honoraria. Hussain:BMS: Consultancy, Honoraria.
Outcome of Second Allotransplantation for Relapsed Hematologic Malignancies After Stem Cell Transplantation
Authors: Tan Tran-Der , Wu Mau-Ching , Chiou Lun-Wei
Published: October 2019

Abstract 4461

Background

Allogeneic or autologous stem cell transplantation is a curative therapy for hematologic malignant disease including leukemia, lymphoma, and myeloma. However, the most common cause of failure is disease relapse and then the prognosis is grim and life expectancy is limited. For selected patients in second remission after salvage treatment and performance status is good enough, second allotransplant is another chance to achieve durable survival.

Method

This is a retrospective study in the past 7 years. For relapsed hematolgic malignancy patients after first stem cell transplantation and the ECOG performance status is 0 or 1, we treated with reduced intensity (RIC) or myeloablative conditioning (MAC) regimens directly or after salvage chemotherapy to induce second remission.

Results

We treated 24 patients with salvage allogeneic stem cell transplantation including 23 underwent second and one underwent third transplant between September 2005 and October 2011. The follow-up period is between 10 and 82 months. Patients median age is 40 with range between 23 and 59 with male to female 15/9. Disease entities include 10 AML, 5 ALL, 1 CML BP, 3 NHL, 4 HL, and 1 myeloma. The median duration between first transplant and disease relapse is 13.1 months (range between 2.5 and 52 months). The median interval between first and second transplant is 17.4 months (range between 5 and 64 months). The 5-year overall survival rate is 37% for all 24 patients and 55% for the 10 AML patients.

Conclusion

Second allogeneic stem cell transplant is feasable and durable survival is still promising for selected relapsed patients after first transplantation but the treatment modality is very individualized either RIC or MAC allotransplant according to patients disease entity and disease status.

Disclosures:

No relevant conflicts of interest to declare.
Outcomes of Salvage Autologous Versus Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Relapsed After Initial Autologous Hematopoietic Cell Transplantation
Authors: Byrne Michael T. , Dai Yunfeng , Moreb Jan , Wirk Baldeep
Published: October 2019

Abstract 4464

BACKGROUND:

Standard therapy for multiple myeloma (MM) includes initial autologous hematopoietic cell transplantation (autoHCT1) but this is not curative and most patients will relapse. Data on salvage autoHCT2 or allogeneic HCT (alloHCT2) are limited and the optimal salvage strategy is unknown.

METHODS:

Retrospective review of MM patients over 18 years of age who relapsed after autoHCT1 and underwent salvage autoHCT2 or alloHCT2 between 1995–2011 at our institution. Tandem auto-autoHCT or auto-alloHCT were excluded. Disease response was defined by the International Myeloma Working Group criteria and assessed 100 days after HCT2.

RESULTS:

Patient characteristics of autoHCT2 (N=27) and alloHCT2 (N=19) (Table 1) were not significantly different except the alloHCT2 median age was significantly lower (54 years) than for autoHCT2 (62 years) and more alloHCT2 patients had KPS 70% or more. Median followup of both groups was 57 months. Complete and very good partial remission (CR/VGPR) improved from 7% to 56% after autoHCT2 and from 26% to 37% after alloHCT2. Of 15 patients with progressive disease (PD) who had autoHCT2, 5 achieved CR/VGPR with 7 PR. Nonrelapse mortality (NRM) at 1 year was 3.7% for autoHCT2 and 5.3% for alloHCT2 (p=.901). Median progression free survival (PFS) and overall survival (OS) for autoHCT2 (19 months, 23 months) and alloHCT2 (6 months, 19 months) were not significantly different (p=0.156 and p=0.255). On multivariate analysis, time from autoHCT1 to relapse less than 1year vs. 1year or more (HR 24.81 [95% CI 2.4–249.9]) and no maintenance therapy vs. given after autoHCT2 (HR 12.19 [95% CI 2.5–249.9] impacted OS after autoHCT2. On multivariate analysis, only time from autoHCT1 to relapse less than 1 year vs. 1 year or more (HR 18.55 [95% CI 2.28–150.57]) impacted PFS after autoHCT2. For alloHCT2, no factors impacted NRM, PFS or OS including chemosensitivity, acute/chronic GVHD, donor lymphocyte infusion, antithymocyte globulin, reduced intensity vs. myeloablative conditioning, matched sibling or unrelated donor, time from autoHCT1 to relapse less than 1 year vs. 1 year or more. For those with relapse from autoHCT1 less than 1 year vs. 1 year or more undergoing autoHCT2, median OS was 15 months (0–53) vs. not yet reached (p=0.003) and median PFS was 5 months (0–49) vs. not yet reached. (p=0.002) Major causes of death for alloHCT2 were PD (n= 5), GVHD (n=3), while for autoHCT2, PD (n=10), infection (n=3).

CONCLUSIONS:

Salvage autoHCT2 and alloHCT2 are both feasible for patients with post autoHCT1 MM relapse. Relpase 1 year or more from autoHCT1 predicts for better PFS and OS in the autoHCT2 group. Those with progressive disease can also be salvaged by autoHCT2. Maintenance therapy after autoHCT2 is beneficial and should routinely be used.

Disclosures:

No relevant conflicts of interest to declare.
Prognostic Value for Survival of Serum Ferritin Levels Over Time After Allogeneic Hematopoietic Cell Transplantation
Authors: Nakamae Mika , Nakamae Hirohisa , Koh Hideo , Nakane Takahiko , Nishimoto Mitsutaka , Hirose Asao , Hino Masayuki
Published: October 2019

Abstract 4466

A significant association between iron overload prior to allogeneic hematopoietic cell transplantation (HCT) and worse prognosis following HCT has been reported. In most previous reports, the serum ferritin level before HCT was used as a surrogate marker of iron load. However, serum ferritin level is known to be increased by acute inflammation, including that due to infection, and/or active hematological diseases. The prognostic value of serum ferritin level has not been evaluated taking into consideration the influence of acute inflammation. In addition, little is known about changes in serum ferritin levels following HCT or the prognostic value for survival after HCT, particularly in the late period post HCT.

Here we comprehensively evaluated the impact of serum ferritin level after HCT as well as pre HCT on survival. We retrospectively studied 204 evaluable patients who had undergone HCT in our institute between February in 2004 and December in 2011, and who had available serum ferritin data pre HCT (median age 46, males 114 and females 90). The median follow-up period among surviving patients was 1023 days. We analyzed the impact of serum ferritin level pre HCT on overall survival after adjusting for various positive and negative acute phase reactants including haptoglobin, fibrinogen, CRP and serum albumin levels in multivariate analysis. On univariate analysis, serum ferritin level pre HCT significantly affected overall survival (ferritin per 100 ng/ml, HR: 1.003, p=0.008) and overall survival significantly worsened as serum ferritin level pre HCT increased (p for trend =0.01). However, after adjustment for haptoglobin or serum albumin levels, the relationship between serum ferritin pre HCT and survival was no longer statistically significant.

Disclosures:

No relevant conflicts of interest to declare.
Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation From HLA-Mismatched Unrelated Donors
Authors: Koclega Anna , Markiewicz Miroslaw , Siekiera Urszula , Dobrowolska Alicja , Mizia Sylwia , Dzierzak-Mietla Monika , Zielinska Patrycja , Sobczyk-Kruszelnicka Malgorzata , Kyrcz-Krzemien Slawomira
Published: October 2019

Abstract 4475

Introduction:

Anti-HLA Antibodies (Abs) are considered an important factor in solid organ transplants and transfusion medicine, but role of humoral arm of immunological response to HLA antigens in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unknown. Large polymorphism and immunogenicity of HLA-antigens and heterogeneity of anti-HLA Abs warrant the need of such investigation. The purpose of this study was to define presence and profiles of anti-HLA Abs detected before or after allo-HSCT from HLA-mismatched unrelated donors and their impact on allo-HSCT results.

Material and methods:

35 HLA-mismatched donor/recipient pairs entered the study. Indication for allo-HSCT was: ALL (7pts), AML(18pts), CML(5pts), SAA(2pts), CLL(1pt), MDS(1pt) and PNH (1pt). Preparative regimen was myeloablative in 33pts (94.3%) and reduced in 2pts (5.7%). Standard GVHD prophylaxis consisted of cyclosporine, methotrexate and pre-transplant anti-thymocyte globulin (34pts) or Alemtuzumab (1pt). HLA A, B, C, DR, DQ alleles were PCR-typed. 21(60%) pts had mismatch of single HLA-antigen: A-4(11.4%), B-1(2.8%), C-13(37%), DQ-3(8,5%); 10(28.5%) pts had mismatch of single HLA-allele: A-3(8.5%), B(11.4%), DQ-3(8.5%); 4 pts had double antigenic (A+C and A+DQ) or combined antigenic/allelic (A/B and C/A) HLA mismatches. Anti-HLA A, B, C, DR, DQ, DP Abs were identified in sera collected before start of the conditioning treatment and +30 days, +100 days and 1 year after allo-HSCT with use of automated DynaChip assay utilizing microchips bearing purified class I and class II HLA antigens.

Results:

Anti-HLA Abs pre-formed before allo-HSCT were detected in 17(48.5%) pts: against class I, II or both in 6(35%), 4(24%) and 7(41%) pts. Anti-HLA Abs were detected after allo-HSCT in 25(71.4%) pts, against class I, II or both in 9(36%), 3(12%) and 13(52%) pts, respectively. In 7 pts anti-HLA Abs were not detected neither before nor after allo-HSCT. Anti-HLA Abs directed against the mismatched HLA antigens were observed in 4 pts before and in 10 pts after allo-HSCT, no anti-HLA Abs specific against mismatched alleles were detected. Allo-HSCT results obtained in studied subgroups are presented in the Table below:

Conclusions:

Our preliminary results indicate that anti-HLA Abs are present pre- or post-transplant in mismatched allo-HSCT recipients and may be potentially responsible for the occurrence of complications, what needs to be further investigated and analyzed.

Disclosures:

No relevant conflicts of interest to declare.
Effect of Antithymocyte Globulin Dosage for Prophylactic Gvhd On Epstein-Barr Virus Reactivation and Diseases in Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Yu Guo-pan , Liu Qifa , SUN Jing , Xuan Li , Wu Meiqing , Liu Xiaodan , Xu Dan , Meng Fan Yi , Zhou Hongsheng , Huang Fen
Published: October 2019

Abstract 4486

Background:

Antithymocyte globulin (ATG) is one of the main risk factors for Epstein-Barr virus (EBV) reactivation and disease in allogeneic hematopoietic stem cell transplantation (allo-HSCT), however, whether there is a correlation between ATG dose and EBV reactivation is unsure. Aim of this single-center prospective study is to explore the relationship between ATG dose and EBV reactivation in allo-HSCT.

Methods:

Ninety-nine patients with hematologic malignancies underwent allo-HSCT and administration of ATG for graft versus host disease (GVHD) prophylaxis were enrolled in this study in Nanfang hospital from February 2008 to February 2012. Sixty-one patients were unrelated donor transplants, thirty-eight were HLA-mismatched related donor transplants. GVHD prophylactic regimen was cyclosporine A+Methotrexate+ATG. According to donors' HLA matching, we chose three dosage groups of prophylactic ATG: low dose group with ATG dose of 5.0∼6.0mg/kg (n=28), medium dose group with ATG dose of 7.0∼8.0mg/kg (n=55), and high dose group with ATG doses of ≥10mg/kg (n=16). The levels EBV-DNA in plasma were regularly monitored by quantitative real-time polymerase chain reaction (RQ-PCR).

Results:

With a median follow-up of 21 (range, 1–50) months post allo-HSCT, the cumulative incidence of EBV viremia and EBV-associated diseases was 17.6% (5/28) and 17.6% (5/28) in low dose group, respectively, with 32.7% (18/55) and 29.1% (16/55) in medium dose group, respectively, with 50.0% (8/16) and 31.3% (5/16) in high dose group, respectively. There were statistical significances of the incidence (χ2□□9.555, P=0.008). Logistic regression models showed that ATG prophylaxis was one of the main risk factors for EBV infection (RR=16.728, P=0.000) while bivariate correlation analysis presented that the incidence of EBV reactivation was positively correlated with ATG prophylaxis dosage (rpearman = 0.452, P = 0.000). The cumulative incidence of high degree (II∼IV°) aGVHD was 35.7% (10/28) in low dose group, with 39.6% (21/53) in total and 50.0% (6/12) in relapsed leukemia with HLA-mismatched related transplantation in medium dose group, with 68.8% (11/16) in high dose group. There were not statistical significances of the incidence (χ2□□6.971, P=0.137).

Conclusion:

EBV reactivation might be positively correlated with ATG prophylaxis dosage. According to donors' HLA matching, reducing ATG prophylaxis dose appropriately could prevent EBV reactivation in allo-HSCT without increasing high degree aGVHD.

Disclosures:

No relevant conflicts of interest to declare.
Impact of Pretransplant Donor and Recipient Cytomegalovirus Serostatus On Outcome for Multiple Myeloma Patients Undergoing Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation
Authors: El-Cheikh Jean , Devillier Raynier , Crocchiolo Roberto , Furst Sabine , Calmels Boris , Faucher Catherine , Stoppa Anne Marie , Granata Angela , Oudin Claire , Ladaique Patrick , Lemarie Claude , Venton Geoffroy , Bouabdallah Reda , Zandotti Christine , Berger Pierre , Chabannon Christian , Blaise Didier
Published: October 2019

Abstract 4496

Purpose:

To investigate the impact of pre-transplant CMV serostatus of donor or recipient on outcome of patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-SCT) for Multiple Myeloma (MM).

Patients and methods:

We retrospectively followed 99 consecutive patients who underwent reduced-intensity conditioning (RIC) Allo-SCT for MM in our cancer centre at Marseille between January 2000 and January 2012. Based upon CMV serostatus, patients were classified as low risk (donor [D]-/recipient [R]-) 17 patients (17.1%), intermediate risk (D+/R) 14 patients (14.1%), or high risk – either (D-/R+) 31 patients (31.3%) or (D+/R+), 37 patients (37.3%).

Results:

Cumulative incidence of CMV reactivation was 39% with a median time of 61 days (26–318). Three patients (3%) developed CMV disease. Two factors were associated with CMV reactivation: CMV serostatus group (low: 0% vs intermediate: 29% vs high: 50%; p=0.001) and the presence of grade II–IV acute GvHD (Hazard Ratio: HR=2.1 [1.1–3.9]). Thirty-six of the 39 patients (92%) with CMV reactivation did not present positive detection of CMV after a 21-day median duration preemptive treatment with ganciclovir. Cumulative incidence of day 100 grade II–IV acute GvHD, 1-year chronic GvHD and day 100 transplantation related mortality (TRM) were 37%, 36% and 9%, respectively. CMV reactivation and serostatus were not associated with increased GvHD and TRM or short survival. Only the presence of acute GvHD as a time dependent variable was significantly associated with increased TRM (p=0.005). Two-year overall and progression free survival were 56% and 34%, respectively.

Conclusion:

Donor and recipient CMV serostatus and acute GvHD are independent factors for increased CMV reactivation in high-risk MM patients undergoing RIC Allo-SCT. However, we did not find any influence of CMV reactivation on post transplantation outcome. CMV monitoring and pre-emptive treatment strategy could in part explain these results. Novel prophylactic measures such as immunotherapy and drug prophylaxis need to be considered in this specific group of patients, warranting further prospective studies.

Legend:

CR, complete remission; VGPR, very good partial remission; PR, partial remission, PD, progressive disease; Flu, fludarabine; Bu, busulfan; ATG, antithymocyte globulin; CR, complete remission; VGPR, very good partial remission; PR, partial remission, PD, progressive disease; MRD, matched related donor; URD, unrelated donor; GVHD, graft versus host disease; CSA, cyclosporine A; MMF, mycophenolate mofetyl.

Disclosures:

No relevant conflicts of interest to declare.
Inhibition of the Renin Angiotensin System During Autologous Stem Cell Transplant Does Not Impact Time to Engraftment □s€
Authors: Kumar Anita J. , Carver Joseph R , Frey Noelle V.
Published: October 2019

Abstract 4502

Background:

The renin angiotensin system modulates hematopoiesis via local effects in the bone marrow. Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) may adversely impact hematopoiesis and time to engraftment in patients undergoing stem cell transplant (SCT). Our study assesses whether the use of ACEi or ARBs delays time to engraftment in patients with multiple myeloma undergoing a melphalan based autologous SCT.

Methods:

A retrospective review of 58 patients who underwent autologous SCT with a melphalan 200 mg/m2 conditioning regimen for multiple myeloma between January 1 and December 31, 2010 was performed. Neutrophil engraftment was defined as an absolute neutrophil count greater than or equal to 500 cells/uL that persisted for at least three days. Platelet engraftment was defined as achieving platelets of at least 20,000 cells/uL that persisted for at least three days. Time to engraftment was defined as number of days from Day 0 of SCT to the first day of platelet or neutrophil engraftment.

Results:

Of 58 evaluable patients, 47 underwent autologous SCT without an ACEi or ARB (control group), and 11 patients were given an ACEi or ARB (treatment group). Mean time to neutrophil engraftment was 11.5 days in the control group, and 11.3 days in treatment group (p=0.6). Mean time to platelet engraftment in control group was 13.5 days and 15.1 days in treatment group (p=0.2). There was no statistically significant difference between groups in time to neutropenic fever and length of hospital stay.

Conclusion:

Our study demonstrates no significant difference in time to engraftment, incidence of neutropenic fever, or length of hospital stay between patients receiving ACEi or ARBS compared to control subjects. We demonstrate that use of low to moderate dose ACEi or ARB is not associated with prolonged time to engraftment and is safe to use in patients undergoing autologous SCT for multiple myeloma.

Disclosures:

No relevant conflicts of interest to declare.
Combined Transplantation of Bone Marrow and Umbilical Cord Blood of Same Sibling in Twenty Three Children with Beta-Thalassemia Major
Authors: Xuedong Wu , Chunfu Li , Feng Xiaoqin , He Yuelin , Zhou Xiaohui , Liu Qifa
Published: October 2019

Abstract 4506

Objective:

To investigate the effect of transplantation using bone marrow plus umbilical cord blood from same sibling in children with β-thalassemia major (TM).

Methods:

Twenty three TM patients undergoing transplantation of bone marrow and umbilical cord blood of same sibling aged from 4.0 to 12 years, 13 boys and 10 girls, were recruited at the Department of Pediatrics, Nanfang Hospital, Southern Medical University from January 2005 to June 2012. The patients were classified into three classes, class¢ñ to class ¢ò 22 cases and class ¢ó 1 case. Donors ranged 1–4 years received 10 Ìg/kg per day of subcutaneous granulocyte colony-stimulating factor (G-CSF) for 5 consecutive days. Bone marrow was harvested on the fifth day. Bone marrow and umbilical cord blood of the same sibling then were transfused into the patient.

Results:

Recovery of hematopoiesis was gained in all patients 4 weeks following transplantation. Seventeen patients suffered from infection of different degree. Six patients developed mild venous occlusive disease. Four patients developed grade¢ñacute graft-versus-host disease (GVHD), and one developed grade¢ñchronic GVHD. Of twenty three patients, twenty survived, three died of whom, one died of lung infection and heart failure 32 days following transplantation, one died of organ failue on 47days after transplantation, and the other one died of lung fugal infection 22 months after transplantation.

Conclusion:

Combined transplantation of granulocyte colony-stimulating factor primed bone marrow and umbilical cord blood of same sibling in children with β-thalassemia major is safe and effective with promising results. However, complications should be paid high attention following transplantation.

Disclosures:

No relevant conflicts of interest to declare.
HLA-Haploidentical HSCT with Post-Transplant Cyclophosphamide for Severe Aplastic Anemia
Authors: He Yuelin , Li Chunfu , Wu Xuedong , Zhou Xiaohui , Feng Xiaoqin , Liu Huaying , Liu Qifa
Published: October 2019

Abstract 4510

Objective

To investigate the effect of pretransplantation donor lymphocyte infusion (DLI) and posttransplantation cycolphosphamide (CY) to prevent graft rejection and graft-versus-host disease (GVHD) after bone marrow transplantation plus peripheral blood stem cell transplantation from HLA-haploidentical mismatched related donors.

Methods

Four patients (median age, 11 years; range, 8–15 years) with severe aplastic anemia and all of them had HLA-haploidentical donors more than or equal to 2/8 HLA (HLA-A, B, C and DRB1) mismatched at antigen level. The conditioning regimen consisted of pretransplantation DLI (Lymphocytes, 1×10e7/kg at day -9); 40mg/m2/day of fludarabine (day-6 to -2); 3.2mg/kg/day of Busulfex (day-6 and -5); 10mg/kg/day of Thiotepa (day -4) and 50mg/kg/day of Cy on day -7, 14.5mg/kg on day-3,-2 and 40mg/kg on day +3,+4, respectively. The prophylaxis of acute GVHD consisted of tacrolimus and mycophenolate mofetil. The median follow-up time is 5 (rang: 3–6) months.

Results

The median times to neutrophil (>500/ÌL) and platelet recovery (>20,000/ÌL) were 21 and 23.5 days, respectively. No acute GVHD and Chronic GVHD were, so far, observed for all patients and were survive without SAA.

Conclusion

Posttransplantation cyclophosphamide for the prophylaxis of acute GVHD was safe and effective.

Disclosures:

No relevant conflicts of interest to declare.
Effect of KIR Ligand Mismatched SCT for Infantile ALL with MLL gene Rearrangement: A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)
Authors: Miyamura Takako , Hirayama Masahiro , Sugita Kanji , Watanabe Tomoyuki , Ishii Eiichi , Koh Katsuyoshi , Kato Koji , Saito Akiko Moriya , Horibe Keizo , Tsurusawa Masahito , Tomizawa Daisuke
Published: October 2019

Abstract 4543

Introduction:

Acute lymphoblastic leukemia (ALL) in infants with MLL gene rearrangement shows poor prognosis and its treatment strategy has not been established. The MLL03 study in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) consisted of the HLA-identical related bone marrow transplantation (BMT) or unrelated cord blood transplantation (CBT) within 4 months after intensive chemotherapy. However, it has not been elucidated whether the stem cell transplantation (SCT) at the early stage of treatment could improve the prognosis of infantile ALL. Recently, the graft- versus- leukemia (GVL) effect in KIR ligand mismatched SCT has been reported in several hematologic malignancies. The purpose of this study is to clarify the effect of KIR ligand mismatched SCT for infantile ALL.

Subjects and Methods:

Twenty-three of the 63 infants with MLL gene rearranged ALL who were registered in the MLL03 study and undergone SCT from February 2004 to January 2009, were evaluated. The prognosis and SCT-related complications were analyzed in patients with KIR ligand matched (n=18) and mismatched (n=5) SCT.

Results:

Overall survival rate (OS) in the KIR ligand matched group was 58.3% (95% CI, 31.3 – 77.8%), while all of the KIR ligand mismatched group have survived (p=0.10). Event free survival (EFS) was 44.4% (95% CI, 21.5 – 65.1%) in the KIR ligand matched group and 80.0% (95% CI, 20.3 – 96.9%) in the KIR ligand mismatched group (p=0.18). Acute GVHD (grade 2 to 4) was detected in 3 patients in the KIR ligand matched group, and 2 in the KIR ligand mismatched group (p=0.54). Two patients in the KIR ligand matched group and 1 in the KIR ligand mismatched group showed chronic GVHD, but it was all mild. Three patients who relapsed after KIR matched first SCT underwent second SCT with KIR mismatched cord blood, and all have survived without relapse.

Discussion:

Our study suggests the effect of KIR ligand mismatched SCT to prevent relapse and improve prognosis of infantile ALL, although no significant difference was observed because of small number of patients in each group. In addition, serious adverse events including GVHD were not detected in KIR ligand mismatched group. We conclude that NK cell mediated GVL effect associated with KIR ligand mismatch might improve the prognosis of infantile ALL after SCT, and therefore should be evaluated as a front-line treatment strategy to improve the prognosis of infants with MLL gene rearranged ALL.

Disclosures:

No relevant conflicts of interest to declare.
Cytarabine Either with Induction or Conditioning May Improve Outcomes Among Those Undergoing Autologous Transplantation in First or Second Remission for Mantle Cell Lymphoma
Authors: Shah Bijal D. , Little Bryan J , Cultrera Jennifer , Bello Celeste M. , Sokol Lubomir , Sotomayor Eduardo M. , Tomblyn Marcie , Ayala Ernesto
Published: October 2019

Abstract 4546

Introduction:

Consolidation with autologous transplantation (AutoSCT) may extend progression free survival when administered following initial induction. Published data suggest intensive cytarabine containing induction may improve outcome when administered prior to autologous transplantation.

Methods:

We retrospectively evaluated all patients with MCL transplanted at our institution before 2010. We identified 57 patients, among whom 52 were transplanted in first or second remission.

Results:

21 patients had received a cytarabine containing induction (most commonly R-HyperCVAD), among whom 14 also received cytarabine as a component of conditioning (BEAM+/−R). The most common induction in the remaining patients was R-CHOP. Among the 31 who did not receive a cytarabine based induction, 23 received cytarabine as a component of the pre-transplant conditioning regimen (BEAM+/−R).

The median PFS for those getting cytarbine with induction and conditioning was approximately 28 months (at which time 51% of patients continued without progression). The median PFS for those getting cytarabine with conditioning only was approximately 38 months (at which time 47% continued without progression). Logrank analysis shows no statistically significant difference between these groups (p one-sided = 0.29). Alternatively, those who did not receive any cytarabine had a median PFS of 20 months, with no survival beyond 33 months. Logrank analysis shows this to be inferior to those receiving cytarabine with induction/conditioning (p one-sided = 0.049), as well as among those who received cytarabine with conditioning only (p one-sided = 0.001).

Conclusions:

In the absence of randomized comparisons it is difficult to draw firm conclusions on the role of induction. These analyses would suggest that among those with chemosensitive disease able to proceed to transplant, more modern conditioning with cytarabine containing regimens may make up for lack of exposure to this agent during induction.

Disclosures:

Sokol: Celgene: Honoraria, Speakers Bureau.
An Observation On Clinical Outcomes of HLA-Haplotype Hematopoietic Stem Cell Transplantation with High-Dose and Post-Transplantation Cyclophosphamide for Children Malignancies Hematopathy
Authors: Li Chunfu , He Yuelin , Wu Xuedong , Peng Zhiyong , Feng Xiaoqin , Liu Qifa
Published: October 2019

Abstract 4547

We retrospectively analyzed early clinical outcomes of HLA-haploidentical HSCT with high-dose post-transplantation cyclophosphamide (Cy). Between June 2009 and June 2012, 20 patients with high-risk acute lymphoblastic leukemias (ALL, n = 10, CR1=5, CR>1=2, NR=3), acute myeloid leukemia (AML, n=7, CR1=3, CR>1=1£¬NR=3), chronic myeloid leukemia (CML) (n=1, CR), and lymphoma (n=2, CR) received HLA-haploidentical HSCT. All patients were HLA-mismatched equal to and more than HLA (at antigen level). All patients received conditioning therapy consisted of Busulfan, Cytarabine, Cy, VP-16 (or CCNU, or TT), and/or TBI. GVHD prophylaxis consisted of Cy 50mg/kg (for first 10 cases) or 40mg/kg (for second10 cases) on day 3 and 4, FK506 and MMF. The median follow-up time was 507 days. Donor chimerism was ¡Ý80% on day +60 but there were one patient with bone marrow failure (BMF) and two without platelet engraftment after day 60. The median time to neutrophil and platelet engraftment were 23 days and 25 days respectively, and no significant deference was found out between first 10 cases and second 10 cases. No II-IV acute GVHD was observed. However, the cumulative incidences of grade I and above GVHD were 60% (garde 1–2 acute GVHD was 40%; garde 3–4 acute GVHD was 15%), and chronic GVHD was 20% after DLI because of relapse. The cumulative incidences of relapse and non-relapse mortality (NRM) were 30% and 40% respectively. Cytopenia occurred in most patients within 6 months after transplant. Three-year overall survival and event-free survival are 35% and 30% respectively. Thirteen patients have died. The causes of death included relapse (n=5), infection (n=3), cGVHD (n=1), BMF (n=1), hemorrhagic cystitis (n=1).

Conclusions:

HLA-haploidentical HSCT with high-dose, post-transplantation Cy for malignancies hematopathy is selection of treatment, with less aGVHD or cGVHD, but also with high relapse and NRM.

Disclosures:

No relevant conflicts of interest to declare.
Tyro3, Axl Ve Mer (TAM) Receptors On Surfaces of Mononuclear Cells in Patients with B-Cell Chronic Lymphocytic Leukemia
Authors: Guney Dilvin , Tulunay Aysin , Pepedil Funda , Kaygusuz Isik , Adiguzel Cafer , Tuglular Tülin , Demir Muzaffer , Eksioglu-Demiralp Emel , Uras Fikriye
Published: October 2019

Abstract 4588

Background:

Tyro 3 (Sky), Axl, and Mer receptors are members of the family of tyrosine kinases and Gas6 is their ligand molecule. In some types of cancer, upregulation of Axl/Gas6 indicated a worse prognosis, but an opposite situation was observed in renal “cell” carcinoma. This contradiction may suggest that Axl/Gas6 pathway varies depending on the type of cancer. The objective of this study is to investigate TAM receptors on surfaces of mononuclear cells in patients with B-Cell chronic lymphocytic leukemia (B-Cell-CLL).

Material & Methods:

B-Cell-CLL patients (grade 0–1, according to the classification of RAI), who were not on a drug treatment, were recruited in this study (n= 20; 9 female, 11 male). Their ages were 44 to 74 (mean: 63), and the control group consisted of 13 healthy volunteers (5 female, 8 male), whose age range is 20–89 (mean: 36). Mononuclear cells were isolated by density gradient centrifugation, and then surface TAM receptors were detected by flow cytometry. Mononuclear cell were stained with the primary antibodies against Tyro3, Axl and Mer.

Results:

The percentage of the surface TAM receptors on mononuclear cells from the patient group (25–75% interquartile range): Tyro 3= 25.50 (4.2– 45.62); Axl= 17/55 (5.57– 36.32), and Mer= 19.90 (1.92– 37.55). In the control group the following values were obtained: Tyro 3= 2.60 (1.35–3.25); Axl= 0.9 (0.4–2.6), and Mer= 2.50 (0.35–3.65). The percentage of three of them was significantly higher in the B-Cell-CLL group than those in the control group (P<0.01).

Conclusion:

In conclusion, this preliminary study showed that TAM receptors on surfaces of mononuclear cells are higher in patients with B-Cell-CLL patients than the control group. Gas6/TAM signaling may play a potential role in the pathogenesis of B Cell-CLL. Further studies are required to elucidate the actual role of Gas6/TAM signaling in B-Cell-CLL. Gas6/TAM signaling might be a new strategic goal for the treatment of B-Cell-CLL.

Disclosures:

No relevant conflicts of interest to declare.
GM-CSF and IL-4 Derived Fusion Cytokine Reprograms Leukemic B-Cells to Anti-CLL Effectors
Authors: Deng Jiusheng , Pennati Andrea , Li Pingxin , Yuan Shala , Murphy Jordan , Ng Spencer , Sinha Rajni , Flowers Christopher R. , Galipeau Jacques
Published: October 2019

Abstract 4606

Fusion cytokines derived from GM-CSF and common γ-chain interleukins have potent gain-of-function properties to alter host immune response. Considering leukemic B cells from chronic lymphocytic leukemia (CLL) patients broadly express the IL-4 receptor, we generated a human GM-CSF and IL-4 derived fusokine GIFT4 to test its immune function on CLL-B cells. Unexpectedly, GIFT4 protein reprograms leukemic B cells into anti-CLL effectors with T-helper features. We show that GIFT4 recombinant protein led to IL4R-dependent hyper-phosphorylation of STAT5 in primary human CLL cells. GIFT4 treated CLL B-cells also up-regulated the expression of co-stimulatory molecules CD40, CD80 and CD86. These cells also secreted IL-1b, IL-6, ICAM1 and substantial IL-2. GIFT4-CLL B cells further propelled the expansion of IFN-g-producing CD314+ autologous cytotoxic NK and T cells in vitro. Administration of GIFT4 protein in NSG immune deficient mice decreased the survival of primary CLL cells from patients in murine circulation. Altogether, our data demonstrate that GIFT4 has potent anti-CLL immune function by reprograming leukemic B cells into anti-CLL helper cells. We propose that the newly bio-engineered fusokine GIFT4 could serve as a potential immunotherapeutic for CLL treatment.

Disclosures:

Flowers: Genentech: Membership on an entity's Board of Directors or advisory committees.
First-Line Prescribing Preferences of American Hematology-Oncology Physicians for Patients with CLL: Impact of Age, Co-Morbidities, and Tempo of Disease
Authors: Green Mark R. , Williams Michael E. , Willey Joanne , Scharf Mitchell , Neely Douglas , Heckman Michael G. , Foran James M.
Published: October 2019

Abstract 4608

Background:

FCR has been a preferred 1st line therapy approach in CLL for the past decade. However it is associated with substantial toxicity and not recommended in NCCN guidelines for patients over age 70. We studied the impact of age, co-morbidities, and tempo of disease on 1st line therapy prescribing preferences of American hematology-oncology physicians (AHOP) for patients with CLL.

Methods:

During Feb-March 2012, prescribing preferences of 325 individual AHOP were assessed using a proprietary, live, case-based market research tool (Challenging Cases™). A core case scenario was constructed with variations based on altered age, co-morbidities, and tempo of disease progression prior to initial therapy. Preference data were acquired using blinded audience response technology. Responses for each scenario were obtained prior to any display of participant selections. All sources of research support were blinded. Core scenario: 67y male; CD 38+, ZAP 70+, del 13q and del 11q CLL, adenopathy, lymphocytosis, splenomegaly, anemia (Hgb 9.5 gm) but no thrombocytopenia. Co-morbidities: medication-controlled hypertension, moderate restrictive airways disease, and type 2 diabetes managed with metformin. Modified scenario: same clinical presentation except the patient is 72 years of age. Slower tempo of disease scenario: age 68y, time frame of observation without treatment 3 years from diagnosis, now with disease progression, anemia 10.9 gms, FISH only del 13q.

Results:

A progressive decrease in preference for FCR and commensurate rise in preference for BR as first line therapy occurs as age increases and co-morbidities are present (p<0.001). See table 1

Conclusion:

As age crosses the 70 year threshold and as co-morbidities complicate therapy, there is a statistically significant increase in preference among AHOPs for prescribing bendamustine-rituximab as initial management for patients with RAI stage III CLL.

Disclosures:

Green: Xcenda: Employment; Teva: Consultancy, ownes publically traded shares in Teva Pharmaceuticals through 3rd party investment advisors, ownes publically traded shares in Teva Pharmaceuticals through 3rd party investment advisors Other. Williams:Xcenda: Honoraria. Willey:Xcenda: Employment. Scharf:Xcenda: Employment. Neely:xcenda: Employment. Foran:Xcenda: Honoraria.
Autophagy Regulation and Dysfunction in Bone Marrow Malignancies
Authors: Pericole Fernando V , Lazarini Mariana , Duarte Adriana S. S. , Machado-Neto João , Olalla Saad Sara T.
Published: October 2019

Abstract 4623

Introduction:

Autophagy is a catabolic pathway by which cytoplasmic materials are degraded into the lysosome and it is also a quality control system for proteins and organelles. Autophagy plays an important role in cell adaptation to starvation, hypoxia, cell survival and cancer. Its core molecular machinery is tightly linked to metabolic pathways, such as LKB1/AMPK and mTORC1. Autophagy has been shown to play several important roles in cancer. Indeed, multiple autophagy genes have been characterized as tumor suppressor genes. In hematopoietic system, autophagy is required during myeloid and lymphoid differentiation, terminal erythroid mitochondrial clearance, production of proplatelets and also differentiation of monocytes into macrophages. Interestingly, autophagy seems disturbed in most bone marrow malignancies. Evidence in mice suggests that autophagy suppression (ATG7 or ATG5 knockdown models) in hematopoietic stem cells may be implicated in Acute Myeloid Leukemia (AML) pathogenesis. In Multiple Myeloma (MM), in vitro studies using cell lines showed autophagy activation and lysosome inhibitors (such as chloroquine) are currently been used in various combination treatments in clinical trials.

Aim:

The aim was to characterize the expression of autophagy machinery key genes (BECN1, MAP1LC3A, SQSTM1), as well as hypoxia master regulator (HIF1A) in total bone marrow cells from bone marrow malignancies: myelodysplasia (MDS), MM and AML patients, excluding acute promyelocytic leukemia.

Methods:

BECN1, MAP1LC3A, SQSTM1 and HIF1A levels were verified, by q-PCR, in diagnostic (or without any treatment) BM aspirates from 22 normal donors, 30 MDS (17 low-risk and 13 high-risk, according 2008 WHO classification), 43 AML and 11 MM patients.

Results:

BECN1 gene expression was increased in MM, compared with control group. All other groups did not differ from the control group. Comparing diseases amongst each other, AML had a lower BECN1 expression, compared with low-risk MDS and with MM (Figure 1A).

Disclosures:

No relevant conflicts of interest to declare.
A Novel Hybrid CFH/CFHR1–3 Gene in Atypical Hemolytic Uremic Syndrome
Authors: Hepgur Mehmet F. , Chaudhary Preeti , Sarkissian Sarmen , Smith Richard J. H. , Liebman Howard , Weitz Ilene C
Published: October 2019

Abstract 4644

Background:

Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and renal failure in the absence of Shiga toxin exposure. Dysregulation of the alternative pathway by mutations in complement regulatory proteins or antibodies to these proteins have been implicated in the pathogenesis of the disorder.

Aims:

We report the late onset of aHUS in association with heterozygous deletion of two genes, CFHR1 and CFHR3, and a mutation in CFH, c.497G>T, p.Arg166Leu. The latter mutation has not previously been reported with aHUS.

Methods:

A 20-year-old female whose past history was unremarkable with the exception of a spontaneous abortion 3 months earlier, presented to an emergency room with abdominal pain and bloody diarrhea three days after eating raw fish. Within 4 days of hospitalization she developed MAHA, thrombocytopenia and renal failure. Studies were negative for Shiga toxin and showed an ADAMTS13 level of 40%. A diagnosis of aHUS was made. Treatment was initiated with daily plasma exchange (PE) which was increased to twice daily for 6 weeks. Response was poor. After discontinuing PE, the patient was treated on an IRB-approved compassionate-use protocol with eculizumab 900 mg weekly for four weeks followed by 1200 mg every two weeks.

Results:

The patient responded slowly to eculizumab. PK values of eculizumab were sub-therapeutic at week 4. On week 5, she was switched to the maintenance dose of 1200 mg every two weeks, which resulted in a rapid normalization of her platelet count and LDH, with further improvement of her renal function and normalization of her mental status. The patient is doing well on continued eculizumab treatment. Genetic testing revealed a known copy-number variation (CNV), hemizygosity for CFHR1 and CFHR3, and a mutation in short consensus repeat (SCR) 3 of CFH, p.Arg166Leu.

Summary/Conclusions:

This patient presented with aHUS unresponsive to PE, but responsive to eculizumab treatment. Genetic testing of complement regulatory genes identified a known CNV and a mutation in CFH, p.Arg166Leu. This mutation lies in SCR3 of CFH, a region of the protein important for fluid-phase regulation of the C3 convertase. Although it has been seen in a rare case of dense deposit disease, it has not has not been reported with aHUS. This patient's poor response to PE suggests that additional genetic factors may be present in this patient that affected the course of disorder. Her slow response to eculizumab may have been due to third spacing of the drug secondary to hypoalbuminemia with anasarca as documented sub-therapeutic levels were present on week 4. When the dose was increased to 1200 mg every two weeks, the patient rapidly improved with resolution of the aHUS.

Disclosures:

No relevant conflicts of interest to declare.
Switching From Romiplostim to Eltrombopag or Vice Versa for Immune Thrombocytopenia: Efficacy and Safety in 46 Patients
Authors: Khellaf Mehdi , Viallard Jean-François , Hamidou Mohamed , Cheze Stephane , Lefrere Francois , Fain Olivier , Audia Sylvain , Jardin Fabrice , Gyan Emmanuel , Durand jean Marc , Haioun Corinne , Bierling Philippe , Michel Marc , Godeau Bertrand
Published: October 2019

Abstract 4651

Romiplostim and eltrombopag, the first thrombopoietic receptor-agonists (TPO-RAs) with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, were recently authorized in Europe for adults with chronic ITP. Their efficacies and safety profiles were evaluated in 46 ITP patients who sequentially received both drugs. Thirty-five patients first received romiplostim (romiplostim group), whereas eltrombopag (eltrombopag group) was the first TPO-RA for 11 patients. All but 2 patients had previously received corticosteroids and IVIg, and 70% had been given rituximab without responding. The splenectomy rate was 50% (23/46). Patients were switching from one to the other for the following reasons: lack of efficacy for half of them, platelet-count fluctuations for 11, side effects for 4 and 8 patients' preferences. For 50% to 80% of the patients, switching from 1 TPO-RA to the other effectively impacted the platelet count, with the disappearance of its fluctuations in 54%, and side effects resolved in 100%. In 80% of the patients, the 2 TPO-RAs achieved similar response patterns. Our results confirmed that switching from 1 TPO-RA to the other could be beneficial in clinical practice for patients with severe chronic ITP who failed to respond or experienced adverse events(s) to the first.

Disclosures:

Khellaf: AMgen: Honoraria; Glaxo Smith Kline: Honoraria. Viallard:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Anti-Thymocyte Globulin (ATG) Differentially Depletes naïve and Memory T Cells and Permits Memory-Type Regulatory T Cells
Authors: Xia Chang-Qing , Chernatynskaya Anna , Wasserfall Clive , Looney Benjamin , Wan Suigui , Clare-Salzler Michael , Atkinson Mark
Published: October 2019

Abstract 4670

Anti-thymocyte globulin (ATG) has been used in clinic for the treatment of allograft rejection and autoimmune diseases. However, its mechanism of action is not fully understood. To our knowledge, how ATG therapy affects naïve and memory T cells has not been well investigated. In this study, we have employed nonobese diabetic mouse model to investigate how administration of anti-thymocyte globulin (ATG) affects memory and naïve T cells as well as CD4+CD25+Foxp3+ regulatory T cells in peripheral blood and lymphoid organs; We also investigate how ATG therapy affects antigen-experienced T cells. Kinetic studies of peripheral blood CD4+ and CD8+ T cells post-ATG therapy shows that both populations decline to their lowest levels at day 3, while CD4+ T cells return to normal levels more rapidly than CD8+ T cells. We find that ATG therapy fails to eliminate antigen-primed T cells, which is consistent with the results that ATG therapy preferentially depletes naïve T cells relative to memory T cells. CD4+ T cell responses post-ATG therapy skew to T helper type 2 (Th2) and IL-10-producing T regulatory type 1 (Tr1) cells. Intriguingly, Foxp3+ regulatory T cells (Tregs) are less sensitive to ATG depletion and remain at higher levels following in vivo recovery compared to controls. Of note, the frequency of Foxp3+ Tregs with memory-like immunophenotype is significantly increased in ATG-treated animals, which might play an important role in controlling effector T cells post ATG therapy. In summary, ATG therapy may modulate antigen-specific immune responses through modulation of naïve and memory T cell pools and more importantly through driving T cell subsets with regulatory activities. This study provides important data for guiding ATG therapy in allogenieic hematopoietic stem cell transplantation and other immune-mediated disorders.

Disclosures:

No relevant conflicts of interest to declare.