bluuebunny/crossref_metadata_2025 huggingface dataset:
Osteoclasts Are Involved in the Maintenance of Dormant Leukemic Cells.
Authors: Yokota Asumi , Kimura Shinya , Tanaka Ruriko , Takeuchi Miki , Yao Hisayuki , Sakai Kazuki , Nagao Rina , Ashihara Eishi , Maekawa Taira
Published: October 2019

Abstract 4245

We have previously reported that zoledronic acid (ZOL) had the anti-tumor activity against chronic myelogenous leukemia in the murine models and it could induce apoptosis to leukemic cells (Kuroda, et al. Blood, 2003). ZOL is a widely used agent to treat osteoporosis or hypercalcemia of malignancy because of its activity to induce apoptosis to osteoclasts (OCs), which are specialized cells to resorb the bone matrix. In this study, we hypothesized that OCs might be involved in the survival or the proliferation of leukemic cells in the bone marrow (BM) microenvironment which consists of osteoblasts (OBs), OCs, blood vessels, and so on.

In order to verify our hypothesis, we used the in vitro co-culture system. Ba/F3 wt bcr-abl cells were indirectly co-cultured with the murine OBs, OCs, and/or the bone slices derived from the murine femoral bones in the transwell chambers. OBs and OCs enhanced the proliferation of Ba/F3 wt bcr-abl cells. Interestingly, OCs significantly suppressed the proliferation of Ba/F3 wt bcr-abl cells in the presence of the bone slices. Next, we examined the cell cycle status of Ba/F3 wt bcr-abl cells co-cultured in each condition. Ki-67-negative populations were reported to be in G0 phase, thus 7-AAD and Ki-67 double staining can distinguish population in G0 phase from that in G1 phase. It was revealed that OCs with bone slices increased the Ki-67-negative dormant populations in co-cultured Ba/F3 wt bcr-abl cells. Recently, it has been reported that TGF-β1 is a candidate cytokine that maintain the hibernation state of hematopoietic stem cells in the BM niche. Furthermore, TGF-β1 is one of the major cytokines accumulated in the mineralized bone matrix. Thus we evaluate the TGF-β1 levels in the culture supernatants of OBs, OCs, and/or bone slices by ELISA. The concentrations of TGF-β1 were significantly higher in the supernatants of OBs, OCs, and bone slices, thus it might be suggested that TGF-β1 was released from the bone slices by bone-resorbing OCs (Figure). Furthermore, TGF-β-neutralizing antibody reduced Ki-67-negative dormant populations in Ba/F3 wt bcr-abl cells co-cultured with OBs, OCs, and bone slices.

In conclusion, our in vitro data demonstrate that OCs might maintain the dormant population of leukemic cells in the BM microenvironment and this effect was yielded, in part, by TGF-β1 released from the bone matrix by OCs. It was also suggested that OCs could be an effective target of a novel therapy against minimal residual disease of leukemia, which are thought to be resulted from the dormant population of leukemic cells residing in the BM microenvironment.

Disclosures:

No relevant conflicts of interest to declare.
A Novel Mechanism of Nilotinib-Induced Apoptosis; Sphingolipids.
Authors: Baran Yusuf , Gencer Emel Basak , Camgoz Aylin , Avcu Ferit , Ural Ali Ugur
Published: October 2019

Abstract 4246

Chronic myeloid leukemia (CML) is a hematological malignancy resulting from the reciprocal translocation of chromosomes 9 and 22 that generates BCR/ABL oncogene. Nilotinib is a rationally designed, specific BCR/ABL tyrosine kinase inhibitor. Ceramide is a novel regulator of cell growth and proliferation, differentiation, senescence, cell cycle and also acts a strong apoptotic molecule while its conversion to antiapoptotic glucosyle ceramide (GC) and sphingosine-1-phosphate (S1P) by glucosyle ceramide synthase (GCS) and sphingosine kinase-1 (SK-1) enzymes result in more aggressive and resistant cancers. In this study, we studied the roles of ceramide metabolising genes in nilotinib induced apoptosis and possibility of increasing the sensitivity of BCR/ABL positive K562 and Meg-01 cells to nilotinib through targeting ceramide metabolism.

The cytotoxicity analyses of nilotinib, C8:ceramide to induce de novo generation of ceramides, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) to inhibit GCS and SK1 inhibitor were conducted by XTT cell proliferation assay. The changes in caspase-3 enzyme activity and mitochondrial membrane potential (MMP) were measured by caspase-3 colorimetric assay and JC-1 MMP detection kit, respectively. Expression analyses of ceramide synthase (LASS) genes, SK-1 and GCS genes were performed by RT-PCR.

We have shown that nilotinib induces apoptosis and inhibits cell-cycle progression in K562 and Meg-01 cells in a dose dependent manner. We have shown significant synergistic apoptotic effects of nilotinib in combination with C8:ceramide or PDMP or SK-1 inhibitor by XTT cell proliferation assay in addition to the changes in caspase-3 enzyme activity and changes in mitochondrial membrane potential, as compared to any agent alone. These results revealed that increasing de novo generation of ceramides or inhibiting conversion of ceramides to antiapoptotic GC or S1P increased sensitivity of BCR/ABL CML cells to nilotinib. More importantly, RT-PCR results revealed that there were significant decreases in expression levels of SK1 in response to increasing concentrations of nilotinib. On the other hand increases in expression levels of LASS2, -4, -5, and -6 ceramide synthase genes were determined in a dose dependent manner as compared to untreated controls.

It was shown for the first time by this study that targeting ceramide metabolism in addition to inhibition of BCR/ABL by nilotinib induces apoptosis synergistically in BCR/ABL positive K562 and Meg-01 CML cells.

This study was supported by The Scientific and Technological Council of Turkey

Disclosures:

No relevant conflicts of interest to declare.
Detection of Enzymatic Activity of Free Circulating Tyrosine Kinase in Patients with Chronic Myelogenous Leukemia (CML) and the Demonstration of Lower Levels in Resistant Patients.
Authors: Yeh Chen-Hsiung , Abdool Adam , Bruey Jean-Marie , Albitar Maher
Published: October 2019

Abstract 4247

Tyrosine kinases (TKs) regulate a wide variety of cellular signaling events, and aberrant activation of TKs is directly associated with tumorigenesis and cancer progression. Targeted therapy using TK inhibitors (TKIs) is commonly explored for treating various types of cancers. Measuring TK activities for diagnosis and monitoring of therapeutic efficacy may be particularly important for patients treated with TKIs. In this study, we examined the clinical utility of measurement of free circulating TK (cTK) activity directly from plasma in CML patients. The study included 46 patients with newly-diagnosed CML, 24 drug (imatinib, dasatinib, or nilotinib)-resistant CML patients, and 38 apparently healthy control subjects. Plasma levels of cTK activity were measured using a chromogenic universal TK assay kit in which samples and standards were added to a 96-well microtiter plate immobilized with synthesized poly (Glu-Tyr) peptide substrates. Specific TK activity was determined by spectrophotometry. Measured cTK activity at baseline was ∼1000-fold higher in plasma than in paired serum specimens. Overall, plasma cTK activity was significantly higher in newly diagnosed CML patients (median=802 U/mL, range=18-3932 U/mL) than in healthy donors (median=83 U/mL, range=0.6-853 U/mL) or drug-resistant CML patients (median=202 U/mL, range=17-1215 U/mL) (P<0.001). In drug–resistant CML patients, plasma cTK activity was closely correlated with cellular BCR-ABL1 kinase activation, as indicated by downstream phospho-CRKL (P=0.0005) and phospho-STAT-5 (P=0.003) levels. TKI treatment of these patients also resulted in a corresponding decrease in cTK activity over time reflecting response to therapy. Nevertheless, cTK activity was not associated with BCR-ABL1 expression level and was independent of BCR-ABL1 mutation type. In conclusion, measuring circulating TK activity in plasma/serum may reflect the leukemic cells in CML patients and can be used to evaluate response to therapy. In addition, our plasma results support previous data showing that resistant cells in CML patients demonstrate lower TK activity as compared with naïve leukemic cells.

Disclosures:

No relevant conflicts of interest to declare.
Cartridge-Based Automated BCR-ABL mRNA Quantification: Towards Simplified Standardisation.
Authors: Cayuela Jean-Michel , Macintyre Elizabeth , Darlington Meryl , Abdelali Raouf Ben , Fund Xavier , Villarèse Patrick , Piterboth William , Tulliez Michel , Raffoux Emmanuel , Sigaux Francois , Rea Delphine , Bories Dominique , Seror Valerie
Published: October 2019

Abstract 4261

Molecular monitoring of chronic myeloid leukaemia patients treated with tyrosine kinase inhibitors (TKI) is essential for therapeutic stratification. In this context inter-laboratory reproducibility is mandatory. This requires standardization and strict alignment to international scale (IS), as established by the IRIS laboratories. We compared economic and analytical performances, including the possibility of reporting results on the international scale, of an automated cartridge-based assay (Xpert BCR-ABL MonitorTM, Cepheid) to classical non-automated analysis on 181 blood samples from TKI treated CML patients in up to three experienced laboratories. The automated Xpert BCR-ABL MonitorTM assay greatly improved reproducibility between non standardized laboratories. Reproducible sensitivity covered 5 logs, on condition that pre-analytical delays were less than 6 hours. Results were convertible to the international reporting scale. Assessment of average costs showed that this automated assay could be economically relevant for annual activity levels below 300, although cost stability was achieved at 600, compared to 1200 annual tests for non-automated testing. The Xpert BCR-ABL MonitorTM assay could therefore be used in local laboratories for routine quantification of e13/e14-a2 transcripts and might contribute to simplified standardization. However, its prognostic impact relative to non-automated quantification remains to be tested prospectively within appropriate clinical trials.

Disclosures:

No relevant conflicts of interest to declare.
Imatinib as Front-Line Treatment in Chronic Myelogenous Leukemia: How Important is the Achievement of Complete Cytogenetic Response after 3 Months?
Authors: Latagliata Roberto , Breccia Massimo , Carmosino Ida , Vozella Federico , Volpicelli Paola , Stefanizzi Caterina , Santopietro Michelina , Cuia Rosa De , Nanni Mauro , Mancini Marco , Alimena Giuliana
Published: October 2019

Abstract 4271

The achievement of Complete Cytogenetic Response (CCyR) (Ph+ cells 0%) with Imatinib treatment still remains the most important objective in Chronic Myelogenous Leukemia (CML) patients. According to The European Leukemia NET guidelines, CCyR should be achieved within the 12th month of treatment while at 3 months of treatment the goal should be complete haematological response. To address the prognostic role of the early achievement of CCyR, we revised 108 chronic phase CML patients [M/F 57/51, median age 54.9 years, interquartile range (IR) 40.8 – 68.1] treated with front-line Imatinib at our Institution from June 2002 to June 2008 who had evaluable karyotype after 3 months of treatment. At onset, median WBC and PLT counts were 78.4 × 109/l (IR 34.0 – 135.9) and 399 × 109/l (IR 282 – 585), respectively. Sokal risk score was low in 52 patients (48.1%), intermediate in 49 (45.4%) and high in 7 (6.5%); a short pre-treatment phase (< 3 months) with Hydroxyurea was administered to 94/108 patients (87%). After 3 months of Imatinib treatment, 84 patients (77.7%) achieved CCyR while 24 patients (22.3%) still presented Ph+ metaphases (median value 40%, IR 20 - 80) at cytogenetic analysis. At univariate analysis, factors with a negative prognostic impact on achievement of CCyR at 3 months were palpable spleen enlargement (p=0.002), WBC count at onset > 100.0 × 109/l (p=0.01) and pre-treatment with Hydroxyurea (p=0.032); on the contrary, sex, age, Sokal risk score and PLT value did not appear to affect early CCyR achievement. Among the 84 patients in CCyR after 3 months, there were 10 failures during follow-up (6 cytogenetic relapses, 2 molecular relapses and 2 evolution to blastic phase); among the 24 patients who did not achieve early CCyR, there were 12 failures during follow-up (9 primary resistances and 3 cytogenetic relapses). The difference in the incidence of failures during follow-up in the 2 groups was highly significant (p<0.001). In conclusion, the achievement of CCyR at 3 months seems unrelated to traditional prognostic factors (Sokal); furthermore, in our experience it appears to have an important prognostic role, as patients not achieving it showed a significantly higher rate of failures during the follow-up.

Disclosures:

No relevant conflicts of interest to declare.
Long-Term Outcome of Imatinib Treatment in Chronic Myeloid Leukemia (CML) Patients in Shanghai: An International Patient Assistance Programs (GIPAP) Analysis.
Authors: Wang Ai-hua , Zhou Li , Zheng Yu , Li Jun-min , Shen Zhi-Xiang , Hu Jiong
Published: October 2019

Abstract 4275

Imatinib as an oral Bcr-Abl tyrosine kinase inhibitor is approved as first-line therapy for patients with CML chronic phase (CP), accelerated phase (AP) and blast crisis (BC). As the appointed clinical center for the International Patient Assistance Programs (GIPAP) program, a total of 339 CML patients with CML-CP (n=274), AP (n=30) and BC (n=35) were registered and received imatinib treatment in our center. The starting dose of Imatinib treatment was 400mg daily and dose escalation to 600mg was allowed in patients of CML-AP or BC and in patients who failed to obtained optimal response. All patients were evaluated regularly according to the GIPAP protocol. In this study, we analysed the outcome of Imatinib treatment in these patients in terms of cytogenetic response, overall and progression-free survival and adverse events. The median age was 42 (13-81) years old. The median time from diagnosis to imatinib therapy was 4.4 (0-273) months. The median follow-up was 29 (3-103) months. The overall survival for patients received Imatinib treatment were 92.8±3.1%, 57.3+11.3% and 12.3±9.7% for CML-CP, AP and BC respectively. Among patients with CML-CP, the cumulative complete cytogenetic response (CCyR) were 71.9% at 12 months and 79.9% at the censored follow-up timepoint. In prognosis analysis, there were two major impact factors associated with progression-free survival (PFS) for the CML-CP patients: achievement of CcyR and Imatinib as initial therapy. The estimated 60 month PFS was 87.1±3.7% for patients who achieved a CCyR irrespective of time and only 46.7±1.37% for patients who failed to obtain a CCyR (P<0.0001). For those patients who received imatinib as initial therapy (95.6±1.85%) had a significantly superior PFS than those patients received imatinib as secondary treatment after initial interferon therapy either due to intolerance or failed to obtain optimal response (65.9±6.4%, P<0.0001). Overall Imatinib was well tolerated and no patient switched to other treatment due to toxicity of Imatinib treatment. Overall, Imatinib as initial treatment for CML-CP was effective and safe in the first analysis of GIPAP program in Shanghai.

Disclosures:

No relevant conflicts of interest to declare.
Imatinib Plasma Levels and Its Correlation with Response in Chronic-Phase Chronic Myeloid Leukemia: Experience of One Centre.
Authors: Gutierrez J. Valentin Garcia. , Odriozola Jesús , Herrera Pilar , Lopez Javier , Calbacho Maria , Jimenez-Rolando Marta , Blanchard Maria , Chinea Anabelle , Tenorio Maria , García-Laraña Jose
Published: October 2019

Abstract 4284

Introduction

Imatinib (IM), 400 mg/d. induces durable responses in chronic myeloid leukaemia (CML) in chronic phase (CP). However, although IM-biodisponibility is fairly good, its plasma levels are variable and can not be predicted. Recently, these plasma concentrations have been related both to the dose being administrated and to the cytogenetic and molecular responses. Thus, Imatinib pharmacokinetics could be an issue towards treatment optimisation in CML patients. Recent studies suggest that therapeutic IM plasma levels should be above 1040 ng/dl.

Aims

To evaluate the association between IM dose and throughout plasma levels with different clinical outcomes.

Results

In this study, we looked for an association between plasma concentrations and clinical outcomes in 16/86 CML chronic phase patients who did not achieve optimal responses following the European Leukemia Net guidelines (ELN) (table 1). Patients with optimal responses and treated with the same standard doses were also analysed as a control group. Patients receiving doses above 400 mg showed throughout plasma levels considered as appropriate. In 7 of 16 patients (47.5%) not achieving optimal responses (ELN criteria), plasma levels were below the supposed therapeutic ranges. We have found no evidence for a correlation between clinical risk factors at diagnosis and the measurement of optimal plasma levels.

Conclusions

IM plasma levels are well correlated with IM dose administrated in the patients studied. In almost 50% of patients who did not achieve optimal responses, IM plasma levels were under the ranges considered therapeutic. Probably these are the patients who may benefit of a dose increase. Obviously, to learn more about the practical value of these measurements a longer follow up with a larger number of patients is needed.

Disclosures:

No relevant conflicts of interest to declare.
The Age of Mexican Patients with Chronic Myeloid Leukemia (CML) Ph+ Is Quite Younger Than the Reported in USA and European Series.
Authors: Vargas-Viveros Pablo , Monroy Rafael Hurtado , Cervera Eduardo , Best Carlos , Aguayo Alvaro , Candelaria Myrna
Published: October 2019

Abstract 4291

CML accounts for approximately 15 percent of the cases of leukemia in adults. It has an annual incidence of 1 to 2 cases per 100000, with a slight male predominance. The median age at presentation is about 60 years and the incidence increases as a function of age, as reported in North American, Australian and European series. However, in our country we found a younger age at diagnosis. Herein we report our analysis of the age distribution of the patients included in the Mexican Cooperative Leukemia Group. We analyzed 356 patients with diagnosis of CML Ph+, from January 2001 to December 2008. The data analysis showed a median age at diagnosis of 37 years (range 16 to 64 years), with a male: female ratio of 1.1:1. There is a clear difference of age between Mexican patients with CML and those reported in the referred series (37 vs. 60 years) highlighting a geographical and/or ethnical pattern that may play a role as prognostic factor and response to treatment. Moreover, challenge the multistep theory of carcinogenesis in CML, inspired by the observation that cancer incidence increases as a higher order function of age, explained by an increasing somatic mutations rate with age. Further analysis and long term observation is required.

Disclosures:

No relevant conflicts of interest to declare.
Renal Transplantation for End-Stage Renal Disease Following Bone Marrow Transplantation: A 10-Year Outcomes Review.
Authors: Williams Shelly , Braden Amy , Vasudev Brahm , Palmer Jeanne , Cohen Eric
Published: October 2019

Abstract 4294

Background

The incidence of hematopoietic stem cell transplantations (HSCTs) in the US is increasing dramatically each year. Nephrotoxic agents used in these patients often lead to kidney injury that can be severe and progress to end-stage renal disease (ESRD) requiring long term dialysis or kidney transplant. Kidney transplantation is the best method of renal replacement therapy and maintenance immunosuppression is the mainstay to prevent graft rejection. Immune tolerance is of substantial interest because it obviates the need for long-term immunosuppression.

Methods

We performed a retrospective analysis of nine patients that developed ESRD after HSCT at the Medical College of Wisconsin. Chart review was performed to obtain demographic information and details of the transplants, patient and transplant outcomes, and various renal and HSCT related parameters.

Results

A total of nine patients were reviewed. Patient age at the time of HSCT ranged from 25-40 years. ESRD was caused by bone marrow transplant nephropathy (BMT-Np) in seven patients, HUS/TTP in one patient, and anti-TBM nephritis in one patient. Six patients received their kidney from a living related donor (LRD), whereas two patients received living unrelated renal transplants (LURRTx), and one recipient received a deceased donor transplant. Three of the six LRD recipients had same-donor renal and hematopoietic stem cell (HSC) transplants and did not require post-transplant maintenance immunosuppression. Of the two LURRTx recipients, no maintenance immunosuppression was required for the patient receiving same-donor organs. The deceased donor transplant recipient continues to be on immunosuppression. Follow-up ranges from 12-23 years post HSCT and 3-12 years post-renal transplant. Seven of the nine patients have functioning bone marrow and kidney transplants. Their serum creatinine ranges from 0.77 to 1.7 mg/dL. One patient died 24 months post-renal transplant from metastatic vaginal squamous cell cancer and had a functioning bone marrow and kidney at the time of death. Another patient was lost to follow-up and died of unknown cause, although her renal function 34 months post transplant was excellent off maintenance immunosupression.

Conclusions

Based on our case series, we conclude that the long-term outcome of renal allografts in patients who have received a renal transplant after HSCT is excellent. The overall requirement for immunosuppressive medications in this population is reduced.

Disclosures:

No relevant conflicts of interest to declare.
Clinical Implications of Pulmonary Function Tests in Allogeneic Stem Cell Recipients.
Authors: Ho Moon Joon , Kang Byung Woog , Kim Shi Nae , Lee Soo Jung , Kim Yun Jeong , Suh Jang Soo , Lee Kun Soo , Cho Yoon Young , Park Jae Hoo , Sohn Sang Kyun
Published: October 2019

Abstract 4297

Pulmonary dysfunction is one of major causes of morbidity and mortality in the allogeneic stem cell recipients. From Jun 2002 to Oct 2008, we retrospectively analyzed pulmonary functions (PF) in 116 consecutive patients who received allogeneic stem cell transplantation (SCT) and survived at least 3 months after transplantation. Pulmonary function test was performed at baseline, 3 months, 6 months, 1 year, and annually thereafter. Ventilatory capacity was measured by forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and FEV1/FVC ratio. Lung volume measurements included total lung capacity (TLC), residual volume (RV), and RV/TLC ratio. Diffusion capacity for carbon monoxide (DLCO) was determined with correction for hemoglobin concentration. Of the 116 patients, 63 patients were followed more than 1 year. The patients with acute graft-versus-host disease (GVHD; p=0.011), chronic GVHD (p=0.009), or CMV infection (p=0.410) showed a decline of FEV1 and FEV1/FVC after 1 year of transplantation. TLC and RV/TLC also showed an increasing tendency after 1 year of transplantation which reflected abnormal ventilatory pulmonary function. Conditioning intensity, unrelated donor type, stem cell dose did not adversely affect the pulmonary function. We calculated the lung function score (defined as FEV1 score plus DLCO score; NIH chronic GVHD consensus Project, 2003) at 1 year of transplant and compared it from that of baseline to identify the factors affecting late pulmonary dysfunction. In the multivariate analysis, extensive cGVHD (OR=3.692, 95% CI=1.154-11.818; p=0.028) and previous CMV infection (OR=5.356, 95% CI=1.311-21.882; p=0.019) negatively affected on late pulmonary function. In addition, the patients with early decline of FEV1 more than 10% at 3 months compared to baseline showed a higher incidence of cGVHD during follow-up (p=0.016). In conclusion, patients who had extensive cGVHD or CMV infection had a higher possibility of late pulmonary dysfunction and decline of FEV1 at 3 months of transplantation reflected the development of cGVHD.

Disclosures:

No relevant conflicts of interest to declare.
Low Relapse without Excessive Transplant-Related Mortality Following Allogeneic Stem Cell Transplantation in Patients with High Risk Secondary Acute Myeloblastic Leukaemia and Myelodysplastic Syndromes, Long-Term Outcomes in a Single Centre Experience.
Authors: El-cheikh Jean , Castagna Luca , Furst Sabine , Faucher Catherine , Esterni Benjamin , Ladaique Patrick , Charbonier Aude , Chabannon Christian , Vey Norbert , Blaise Didier
Published: October 2019

Abstract 4308

Allogenic stem cell transplantation (Allo-SCT) as a therapy for secondary acute myeloid leukaemia (sAML) and myelodisplastic syndromes (MDS) is the most powerful treatment option. However, (Allo-SCT) is also complicated by a high risk for treatment-related morbidity and mortality.

We analysed retrospectively the data of 70 patients transplanted at our institution from June 1995 to december 2008, 44 patients (63%) with sAML and 26 patients (37%) with MDS was treated with (Allo-SCT); median age at diagnosis was 41 years, (15-70), and the median age of 42, 5 years (16-70) at transplantation; The conditioning regimen was myeloablative combining (cyclophosphamide and TBI) in 16 patients (23%) and 54 patients (77%) was with a reduced intensity conditioning (RIC) regimens combining fludarabine, busulfan, and antithymocyte globulin; 11 patients (16%) were infused with bone marrow (BM), 55 patients (79%) peripherical blood stem cells (PBSC), and 4 patients (5%) cord blood cells; in 49 cases (70%) donor was a HLA identical sibling and in 21 (30%) was a matched unrelated donor;

41 patients (59%) carried high risk cytogenetic features, like (7q-, 5q-, > 3 alterations), while was normal in 24 patients (34%), and in 5 patients (7%) was unknown. Disease status at transplantation was as follow: CR in 24 patients (34%), 34 patients (49%) was refractory or in progression after treatment, and 12 patients (17%) was with a stable disease.

With a median follow-up of 55 months (3-150), 30 patients (43%) are alive, the overall survival OS at 2 years and 5 years was 48 % and 39% respectively, and after ten years of follow up, OS was 30%, 95%CI [17.8-50.8]. We observed also that 26 % of refractory patients and 54% of patients in CR are alive at five years of transplantation.

The probability of progression after transplantation at five and ten years was 31% with 95%CI [20.-46.5].

2 years and 5 years treatment related mortality (TRM) was 23% and 26% respectively, and no modification at ten year, 95%CI [14.3-37.3]. TRM occurred in 16 patients (23%). Cause of death was; infections in 5 patients (7%), GvHD in 3 patients (4%), GvHD and infection in 3 patients (4%), multi organ failure (MOF) in 5 patients (7%). In multivariate analysis; OS, PFS or TRM, were not influenced by donor type (HLA id sibling vs others), conditioning regimen (RIC vs MAC), and stem cell source (bone marrow vs PBSC).

Allogenic stem cell transplantation can be considered as a good option for the treatment of patients with high risk sAML and MDS when compared with the remission rate at five years of the other nonallogeneic SCT therapies.

Disclosures:

No relevant conflicts of interest to declare.
Early Neurologic Complications After Allogeneic Hematopoietic Stem Cell Transplantation in Children.
Authors: Koh Kyung Nam , Park Meerim , Bae Keun Wook , Kang Hyoung Jin , Im Ho Joon , Moon Hyung Nam , Seo Jong Jin
Published: October 2019

Abstract 4314

Backgrounds

Neurologic complications after allogeneic hematopoietic stem cell transplantation (HSCT) have not been clearly described, especially in children.

Methods

We analyzed the medical records of 194 consecutive children (median: 7.2 years, range: 6 months-18.4 years) who underwent allogeneic HSCT for malignant or non-malignant hematologic disorders at Asan Medical Center between 1998 and 2009.

Results

Donors were matched siblings in 64, unrelated volunteers in 127 and haploidentical mothers in 3. Twenty-eight children (14%, 95% confidence interval[CI]: 9-19) developed neurologic complications within the first 6 months of HSCT. Calcineurin inhibitor associated-neurotoxicity was the most common neurologic complication (n=14), followed by cerebrovascular events (n=6), thrombotic microangiopathy-associated abnormalities (n=2), hypoxic-ischemic brain injury (n=2), CNS infection (n=1), metabolic encephalopathy (n=1), and events of undetermined cause (n=2). Univariate analysis showed that transplant from unrelated donor, peripheral blood grafts and occurrence of acute GVHD (>grade 1) were associated with significant increased risk of neurologic complications. In multivariate analysis, development of acute GVHD (>grade 1) was identified as an independent risk factor for early neurologic complications. Survival at 1-year was significantly inferior in patients who developed neurologic complications within 6 months of transplant (42% [95% CI: 23-61] versus 82% [95% CI: 76-88], p<0.0001).

Conclusion

Neurologic complications are significant clinical problems among children receiving HSCT, contributing to early death after transplant. Immediate diagnostic efforts to detect neurologic events are required in patients with clinically suspicious symptoms.

Disclosures:

No relevant conflicts of interest to declare.
Peripheral Blood Chimerism Can Replace Marrow Chimerism Analyses Following Adult Allogeneic Stem Cell Transplant.
Authors: Rauwerdink Cocav , Tsongalis Gregory J , Hill John M. , Meehan Kenneth R
Published: October 2019

Abstract 4316

Chimerism defines the amount of donor versus recipient hematopoiesis following allogeneic stem cell transplant (SCT). PCR-based analyses of short tandem repeats (STRs) are commonly used and are accurate and applicable to allogeneic transplant recipients. These analyses are performed on peripheral blood and marrow aspirates, but it is not known if it is necessary to analyze both. We performed a retrospective analysis of 42 consecutive adult allogeneic SCT recipients at our institution with available chimerism studies. PCR and capillary electropheresis of microsatellite loci were performed at 30, 60, and 90 days after SCT on both unfractionated blood and unfractionated marrow aspirate. Full donor chimerism (FDC) was defined as 95% or greater donor chimerism. PCR analyses of STRs for chimerism performed on unfractionated blood did not differ from results obtained on unfractionated marrow aspirate at 30, 60, or 90 days post transplant (P<0.0001). Peripheral blood PCR-based chimerism analyses provide similar information as marrow aspirate analyses. Using peripheral blood alone saves the expense of an additional analysis on marrow aspirate and prevents an uncomfortable procedure. These findings provide unique results suggesting larger studies in the adult population are needed to further delineate the role of chimerism analyses following allogeneic SCT.

Disclosures:

Meehan: Berlex Pharmaceuticals: Research Funding.
Life-Threatening Complications Suspected Due to Clinical Pharmacokinetic Interaction Between Cyclosporine A and Triazole Antifungal Agents in Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) Recipients.
Authors: Yang Ting , Fu Danhui , Hu Jianda , Zheng Xiaoyun , Luo Xiaofeng , Qiu Hongqiang , Wu Xuemei , Chen Ruling , Chen Zhizhe
Published: October 2019

Abstract 4319

Background

It is well documented that the co-medication with the triazole antifungal agents is associated with a flattening of the CSA blood concentration profile via the cytochrome P450 3A4 dependent metabolic pathway in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Then it raises the question if the therapeutic monitoring of CsA trough levels is sufficient enough to reflect the drug exposure and to assess the transplant-related complications such as transplant rejection and drug toxicity.

Objectives

To evaluate the tolerability, toxicity and clinical outcome of the co-administration of CSA and triazole antifungal agents in allo-HSCT recipients.

Patients and methods

A retrospective review of the medical records of 104 consecutive patients undergoing allo-HSCT for hematologic malignancies at our transplant center over past 5 years was conducted. The causality of administration of CSA in combination with triazole in 12 cases with life-threatening complications experiencing supratherapeutic trough levels of CSA were identified and analyzed.

Results

In all these 12 patients, the CSA trough levels remained highly than therapeutic range even after gradual tapering of CSA dosage. Shortly after the engraftment, 6 patients (50 %) developed acute graft-versus-host disease (aGVHD) and non-infectious pulmonary complication, and 2 patient (16.66 %) acute graft rejection. Which indicates the trough plasma concentration might be inadequately reflect CSA absorption profile. Whereas, 4 (33.33 %) patients were evaluated with neurological complications, 1 (8.33%) patient cardiovascular complication accompanied by acute renal failure and liver dysfunction, that might be ascribed to CSA-related adverse effects. 10 (83.33 %) out of the 12 patients eventually died, 2 (16.66 %) patient are still alive after graft rejecting. The major causes of death were GVHD related pulmonary injury with fungi infection

Conclusion

Although preemptive CSA dosage reduction and the close monitoring of its whole blood trough levels may minimize the drug-toxicity when co-administration with triazole antifungal agents, the different clinical spectrum and different disease evolution post transplant in this group warn that in the set of hematopoietic cell transplantation with CSA as immunosuppression agent the individual variables influence the drug-exposure and drug-toxicity. Thereof, as clinicians we should not be mislead by trough plasma concentrations as a routine therapeutic drug monitoring in terms of CSA exposure related efficacy or toxicity, especially when CSA in combination with triazole.

Disclosures:

No relevant conflicts of interest to declare.
Preliminary Experience of the Pakistani Network for the Cure and Prevention of Thalassaemia Supported by the Cure2Children Foundation.
Authors: Faulkner Lawrence B. , Shamsi Tahir , Ansari Saqib , Farzana Tasneem , Khalid Sadaf , Clemente Luigi , Yaqub Naila , Zafar Tahira , Kamran Rashid , Iqbal Yasir , Sodani Pietro , Gallucci Cristiano , Erer Buket , Lucarelli Guido
Published: October 2019

Abstract 4331

Since May 2008, the Cure2Children Foundation has supported both financially and professionally a network of centers in Pakistan for stem cell transplantation applied to the cure of thalassemia major, a very prevalent disease with more than 60.000 registered cases in that country. The methodology employed consists of matched-related standard bone marrow transplantation after myeloablative chemotherapy as currently employed at the Mediaterranean Institute of Hematology for younger patients with transfusion-dependent thalassermia (thiotepa 10 mg/kg, busulfan 14 mg/kg and cyclophosphamide 200 mg/kg) followed by GVHD/rejection prophylaxis with prednisone/methotrexate/cyclosporin. Management standards for central venous access, severe pancytopenia, immunosuppression, hospital infection control, and other relevant issues have been addressed by local training as well as with web-based data management and videoconferencing. A total of 15 transplants have been performed to date, 7 at an established center (National Institute of Blood Diseases, Karachi), and 8 at newly developed services (5 at the Pakistan Institute of Medical Sciences, Islamabad, and 3 at Shifa International Hospital, Islamabad).

Patient characteristics

Median age 3.4 years (range 0.9 to 6.2), 7 males and 8 females.

Results

At a median follow up of 135 days (range 17-336), actuarial thalassemia-free survival is 79% and overall survival 93%. So far two patients had a graft failure and are alive and well after autologous reconstitution. One patient died for an intracranial bleed, one developed grade 3 acute GVHD (which responded promptly to steroid therapy), 4 had subclinical CMV activation and one developed pulmonary tuberculosis (currently on treatment and doing well). No case of chronic GVHD has been observed so far.

Conclusions

These preliminary results are comparable to those obtained in western centers, detailed updated clinical and cost analysis will be presented. We believe that this ongoing experience might contribute to extend access to allogeneic transplantation for the cure of low-risk thalassemia children in limited resource settings.

Disclosures:

No relevant conflicts of interest to declare.
HY Disparity Influences Outcomes of HLA-Matched Unrelated Allo-HSCT.
Authors: Markiewicz Miroslaw , Siekiera Urszula , Mietla Monika Dzierzak , Karolczyk Agnieszka , Kruzel Tomasz , Helbig Grzegorz , Krzemien Slawomira Kyrcz
Published: October 2019

Abstract 4337

Introduction

Donor and recipient sex is an important factor that may influence outcomes of HLA-identical allogeneic hematopoietic stem cell transplantation. The rationale of this study was to evaluate the impact of sex-related HY antigen mismatch on results of allo-HSCT from HLA-matched unrelated donors.

Patients and Methods

92 patients treated with 10/10 HLA alleles-matched unrelated allo-HSCT performed in Hematology and BMT center in Katowice in years 2004-2006 entered the study. HY genotyping was performed in the Regional Blood Center with use of Dynal Minor Histocompatibility Antigen Typing Kit. Only immunogenic HY disparities were analysed.

Results

The estimated probability of immunogenic HY mismatches corrected by the frequency of restrictive HLA molecules was 34%. When HY was mismatched in GVH direction (female donor, male recipient), the incidence of cGVHD was increased (66% vs 38%, p=0.02), the relapse rate was decreased (6% vs 23%, p=0.046) and DFS tended to improve (79% vs 44%, p=0.067).

Conclusions

The sex-related HY antigen mismatches in GVH direction influence the results of allo-HSCT from HLA-matched unrelated donors. Results of this study may help to understand why sex difference between the donor and the recipient plays role in the allo-HSCT.

Disclosures:

No relevant conflicts of interest to declare.
Allogeneic Hematopoietic Stem Cell Transplantation for Treatment of Philadephia Chromosome Negative Acute Lymphoblastic Leukemia.
Authors: Qu Shiqiang , Fu Chengcheng , Depei Wu
Published: October 2019

Abstract 4338

Objective

To explore the optimum donor selection of allogeneic hematopoietic stem cell transplantation (allo-HSCT) applied in patients with Philadephia chromosome-negative acute lymphoblastic leukemia(Ph- ALL) and investigate its relevant prognostic factors.

Methods

A total of 48 adult patients with Ph- ALL who had admitted to our hospital and been treated by allo-HSCT from February 2002 to May 2008 were followed up until July 2008. They were divided into match related donor(MRD -HSCT) group, match unrelated donor(MUD-HSCT) and Haploidentical (Haplo-HSCT) group. Clinical characteristics of these groups were retrospectively analyzed. Survival data were analyzed by the Kaplan-Meier method and the prognostic factors were analyzed with the COX regression model.

Results

Of all the 48 cases, 5-year overall survival(OS) was 45.4±8.1%, disease free survival(DFS) was 40.7±7.9%.The 5-year OS and DFS of MRD –HSCT subgroup, MUD-HSCT subgroup and Haplo-HSCT subgroup were 50%±14.4%,53.2%±13.2%, 31.3%±13.6%(p=0.048) and 44.7%±13.3%,41.4%±13.6%,32.1±14.2%(p=0.167), respectively. Haplo-HSCT subgroup 5-year OS lower than other two subgroups, which showed statistical significance. GradeIIto‡W acute graft versus host disease(aGVHD) [p=0.001,RR=6.980] and white blood cell at diagnosis higher than 30×109 /L[p=0.028, RR=2.679]were the risk factor of OS in multiple covariate analysis model. The HSCT type was not independent risk factor of OS.

Conclusion

MUD-HSCT and MRD-HSCT have similar efficacy in adult Ph- ALL. Haplo-HSCT can be a distinct option in High-risk adult Ph- ALL patients without a MRD and MUD.

Disclosures:

No relevant conflicts of interest to declare.
Donor Stem Cell Source Does Not Impact Outcome of High Risk (HR) Acute Myeloblastic Leukaemia (AML) Patients After Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation (RIC-ALLO).
Authors: Furst Sabine , Castagna Luca , Prébet Thomas , Lemarie Claude , Cheikh Jean El , Faucher Catherine , Vey Norbert , Charbonnier Aude , Ladaique Patrick , Chabannon Christian , Blaise Didier
Published: October 2019

Abstract 4339

Allogeneic Stem Cell Transplantation (ASCT) offers a potential curative treatment approach of HR AML patients (pts). Over years, the use of umbilical cord blood (UCB) has become an attractive alternative stem cell source for those pts lacking a suitable HLA matched related or unrelated donor.

The aim of this analysis was to assess the outcome of 50 pts who received a RIC-ALLO in our centre between 2005 and 2008 with a special focus on three different donor sources: identical sibling, unrelated donor or UCB.

All pts had HR AML in complete remission (CR) at time of transplant. HR features were defined as at least one of the following criteria: CR1 with unfavourable cytogenetics, secondary AML, more than one induction chemotherapy for obtaining CR or CR2 and above. Reasons for RIC regimen were older age, unfit physical condition, comorbidities or prior autologous transplant. All pts received a Fludarabine-based RIC regimen with GVHD prophylaxis consisting in CSA alone or CSA and MMF.

The median age of all pts was 51 (range, 19-70) years. 28 pts had identical sibling donors, 7 pts had a matched 10/10 (5 pt) or mismatched 9/10 (2 pt) unrelated donors and 15 pt received a single or double UCBT. Pts characteristics were comparable between the three groups but for pt age [identical sibling group: 52 (range, 35-70) years; unrelated donor group: 61 (range, 50-66) years; UCB group: 44 (range, 19-61) years].

After a median follow-up of 886 (range, 336-1528) days, 20 pts have died (disease=6, treatment related=14) and 8 pts have experienced relapse. Four year OS and EFS for all pts were 57% and 54%, respectively with no significant difference between the 3 groups (2 year OS: 61%, 54% and 66%; 2 year EFS: 59%, 54% and 45% respectively). One year TRM was 20% for the entire group and did not significantly differ between the 3 groups.

Despite the obvious limitations of this small series, results seem to indicate that in this population, donor type does not highly influence outcome. This is quite encouraging as most of the pts lack a compatible sibling donor. This may invite to consider privileging a rapid identification of an alternative donor rather than a given donor type when a match sibling is not available. Thus concomitant search for both graft type should be undertaken in order to perform allo SCT in a larger number of pts otherwise not treated because of early progression as illustrated in the underrepresentation of alternative transplant as compared with familial transplant in this retrospective study (28 familial vs 22 alternative).

Disclosures:

No relevant conflicts of interest to declare.
Outcome of IgD Myeloma After Autologous Hematopoietic Stem Cell Transplantation.
Authors: Qureshi Sofia , Sharma Manish , Hosing Chitra , Mendoza Floralyn L , Shah Jatin , Alousi Amin , Anderlini Paolo , Kebriaei Partow , Khouri Issa F , Popat Uday , Lima Marcos de , Champlin Richard E , Giralt Sergio , Qazilbash Muzaffar H.
Published: October 2019

Abstract 4354

BACKGROUND

Multiple Myeloma (MM) is a clonal disorder of plasma cells characterized by monoclonal immunoglobulin (Ig) secretion. Immunoglobulin D (IgD) MM constitutes <2% of all myeloma cases and is characterized by a younger age, male predominance, frequent extra osseous disease, amyloidosis, renal insufficiency and a poor prognosis. We retrospectively analyzed the outcome of patients with IgD myeloma transplanted at our institution.

METHODS

Between August 1988 and June 2008, 15 patients with IgD MM (13 males, 2 females) received autologous hematopoietic stem cell transplantation (auto HCT) at MD Anderson Cancer Center. Twelve patients received high-dose melphalan (200 mg/m2) as preparative regimen; 3 patients received high-dose melphalan in combination with other agents.

RESULTS

At diagnosis 7/15 (47%) patients had Durie-Salmon stage III disease, 6/15 (40%) had serum creatinine ≥2 mg/dl and 6/15 (40%) had hypercalcemia. Median age at the time of auto HCT was 53 yrs (range 38–64 yrs) and median interval between diagnosis and auto HCT was 12.6 months (range 3-75 months). Prior to auto HCT 11 patients achieved a partial remission (PR), one had a very good partial remission (VGPR), 2 had minimal response (MR) and one patient had no response to induction. Median follow-up in surviving patients was 25 months. Median time to neutrophil engraftment (ANC > 500/dl) was 10 days (range 9–15 days) and for platelet engraftment (>20,000/dl) was 11 days (range 8–16 days). Non-relapse mortality at 100 days was 0%. Complete responses were seen in 6/15 (40%) patients; 3 converted from PR to CR, 2 from MR to CR and one from VGPR to CR. Only one patient progressed within 3 months of auto HCT. Kaplan-Meiers estimates of 3-year progression-free survival (PFS) and overall survival (OS) were 38% and 64%, respectively. Median time to progression was 18 months. One patient with complex cytogenetics including deletion 13q had disease progression 7 months following an auto HCT. He subsequently received an allogeneic transplant, achieved stable disease status and died 11 months later due to progressive disease. Another patient received a second auto HCT for relapse, but died 3 months later due to progressive disease.

CONCLUSIONS

Patients with IgD MM, despite a higher incidence of renal insufficiency and hypercalcemia at diagnosis, can safely receive auto HCT, with overall response rates, PFS and OS comparable to other MM subtypes.

Disclosures:

Shah: Celgene, Amgen, Novartis, Elan: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.