bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Survival after Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation in AML-Patients Is Consistently Sustained and Influenced by Donor Type Selection.
Authors: Sayer Herbert G. , Muegge Lars-Olof , Scholl Sebastian , Schilling Kristina , Klink Anne , Schmidt Volker , Hoeffken Klaus
Published: October 2019

A total of 46 patients (24 female, 22 male) with acute myeloid leukemia (AML) received RIC allogeneic blood stem cell transplants from either fully HLA-compatible family donors (n=14) or unrelated HLA-compatible donors (n=32) between 3/1999 and 3/2007. The unselected consecutive single centre study patients (median age: 52 years, range: 22–64) were at high risk for treatment-related complications (older age, previous infectious complications, impaired organ function). 67% (n=31) of the cohort were not in first remisson but in an advanced status of AML. All patients received 30 mg·m−2 Fludarabine i.v. day −10 to −5, Busulfan 4mg·kg−1 orally day −5 to −4, and 10 mg·kg−1 i.v. Antithymocyteglobulin (ATG-Fresenius®) day −4 to −1 as RIC prior to allogeneic stem cell transplantation. A median of unselected 6.8 x 106 CD-34 positive stem cells (range: 1.9–14.3) were given. GvHD-prophylaxis consisted of Cyclosporin 3mg·kg−1 continuous infusion in case of 10/10 HLA compatibility donor situation (n=34), with the addition of mycophenolate mofetil 2gr. i.v. primarily starting from day +10 in one antigen mismatched HLA-unrelated donor situation (n=12). Nine patients (19.6%) died of therapy related mortality, due to GvHD (n=3), infections (n=4), or both (n=2). Relapses occurred in 18 patients (39%), in five patients even more than one year after transplantation. The median observation time of the study group was 19 months (range: 3–101), the product-limit estimates (Kaplan-Meier) of overall survival (OS) at 36 months were 0.48 (±0.08), of event-free survival (EFS) 0.44 (±0.08), respectively.

Figure Figure

Disease-status (remisson vs. advanced) failed to have a significant impact in OS or EFS, whereas donor status (related vs. unrelated) resulted in OS at 24 months 0.76 (±0.12) for related donors and 0.4 (±0.09) for unrelated donors (p=0.017, log-rank test). RIC with Fludarabine/Busulfan/ATG prior to allogeneic stem cell transplantation results in a consistently sustained long-term outcome for this otherwise adverse patient subgroup, favouring family-matched donor selection.
The Analysis of Chronic GVHD after Cord Blood Transplantation in Comparison with Bone Marrow Transplantation.
Authors: Seo Sachiko , Uchida Naoyuki , Ishiwata Kazuya , Tsuji Masanori , Yamamoto Hisashi , Takagi Shinsuke , Kato Daisuke , Matsuno Naofumi , Masuoka Kazuhiro , Atsushi Wake , Taniguchi Shuichi
Published: October 2019

Backgrounds: Umbilical cord blood can be an alternative stem cell source for the patients with hematological malignancies requiring allogeneic stem cell transplantation. However, little is known about graft versus leukemia/lymphoma (GVL) effect in cord blood transplantation (CBT). Here, we analyzed chronic GVHD (cGVHD) in CBT compared with that in BMT and evaluated the relevance between cGVHD and GVL.

Patients/methods: We retrospectively studied 162 patients who had been free from disease progression for more than 100 days after either unrelated BMT (n=75) or CBT (n=87) at Toranomon Hospital from January 2002 to October 2006. Median age of the patients was 52 years old (BMT vs CBT: 49 vs 53). Underlying diseases were acute leukemia (n=88), myelodysplastic syndrome (n=17), lymphoma (n=39) and others (n=18). Conditioning regimens were mainly composed of Fludarabine 125–180 mg/m2 with several combinations of Melphalan 80–140 mg/m2, Busulfan 8–16mg/kg and/or total body irradiation (4–8 Gy).

Results: The Median observation period after the transplantation was 612 days (range, 109–1944). The cumulative incidence of cGVHD was 84% in BMT and 62% in CBT (p=0.09). The severity of cGVHD was analyzed based on its type; limited or extensive. In CBT, the percentage of the former type was 34% (vs 25% in BMT) and the latter was 23% (vs 48% in BMT). High-risk disease (p=0.03) and preceding acute GVHD(p=0.03) are related to the occurrence of cGVHD. RICBT tended to increase cGVHD compared to CBT using BU/CY or CY/TBI regimen, Multivariative analysis showed that cGVHD increased overall survival (p<0.01) and suppressed recurrence of the disease (p<0.01). During observation period, no patients were died of cGVHD.

Discussion: We demonstrated that cGVHD in CBT is tolerable compared with that in BMT and that the occurrence of cGVHD could result in good prognosis. Our analysis also suggested that CBT could have GVL effect as well as BMT.
Tolerability of PTK787/ZK 222584 in a Phase II Study of Post-Transplant Maintenance Therapy in Patients with Multiple Myeloma Following High-Dose Chemotherapy and Autologous Stem Cell Transplant.
Authors: Mosley James C. , Peles Shachar , Ruddell Alisa , Gao Feng , Abboud Camille , Cashen Amanda , Uy Geoffrey , Westervelt Peter , DiPersio John F. , Vij Ravi
Published: October 2019

Background: Currently, High-Dose Chemotherapy (HDCT) followed by autologous stem-cell transplantation (ASCT) is the standard of care in Multiple Myeloma (MM). This therapy improves overall and event-free survival, but is not curative, necessitating further therapies that will enhance and prolong remission duration. PTK787/ZK 222584 is a potent, orally available, angiogenesis inhibitor that blocks all known VEGF receptors in a dose-dependent fashion. Preclinical studies have demonstrated that PTK/ZK is able to inhibit tyrosine phosphorylation of VEGFR-1 in MM cells, as well as inhibit MM cell migration and proliferation. Based on this, a phase II study was designed to assess efficacy and tolerability of PTK/ZK as maintenance therapy for individuals treated HDCT and ASCT for MM.

Study Design: Patients with MM treated with HDCT and ASCT with persistent measurable paraproteinemia or persistent abnormal serum κ/λ ratio were selected for treatment with PTK/ZK. Primary endpoint is overall response rate and secondary endpoints are time to progression, disease free survival, and safety. Patients were initiated on 750mg daily of PTK/ZK, with doses escalated to 1250 mg daily.

Results: Nine patients have received PTK/ZK and their baseline characteristics are as follows: median number of days on PTK/ZK is 129 (range 3–252); median number of cycles administered is 5 (range 1–14); median age is 57 (range 38–71); stage IIIA (7), stage IIA (1), stage IA (1); IgG isotype (7), IgA isotype (2); median β2-microglobulin level was 1.7 (range 1.2–4.2). Of the nine patients who initially received PTK/ZK, four remain on the medication, three patients have stopped due to progressive disease, and two have stopped due to toxicities. One patient has demonstrated a PR (11%), three patients have SD, and three patients had PD. There have been no deaths. Toxicities are as follows: one patient developed grade 3 elevated ALT as well as motor and sensory neuropathy, one patient developed grade 3 neutropenia, and one patient developed grade 3 prolongation of the QTc interval. Two patients were withdrawn from the study due to toxicities, one with grade 3 prolongation of the QTc interval as well as grade 4 Hypertension, and one patient with grade 4 Hypertension alone. The remaining five patients have had no significant adverse drug events.

Conclusion: Continued patient accrual is underway for analysis of time to progression and disease free survival as well as overall response rate. Bone marrow samples are also being evaluated for change in microvessel density by immunohistochemistry with treatment.
Disease Burden of Chronic Lymphocytic Leukemia within the European Union.
Authors: Watson Louise , Wyld Peter , Catovsky Daniel
Published: October 2019

Introduction: While Chronic Lymphocytic Leukemia (CLL) is considered a rare disease, to our knowledge the current prevalence of the condition within the European Union (EU) member states is not published. Understanding the number of individuals with CLL is vital to assess disease burden within the wider population.

Methods: Using 2002 data from the International Agency for Research on Cancer (IARC), we estimated the number of individuals with CLL (ICD-10 C91.1) from those reported for all leukemias (C91–95) and extrapolated the figures by the population increase within the EU between 2002 and 2006, the last year with fully updated Community population estimates. One-year and 5-year partial prevalence estimates are reported (i.e. the number of individuals still living 1 and 5 years post diagnosis). We then applied proportional estimates from the literature to assess those requiring immediate treatment, those under observation and their likely progression rates.

Results: We found that within the 27 EU states plus Iceland, Norway and Lichtenstein, 1-year and 5-year CLL partial prevalence estimates totalled approximately 13,952 and 46,633 individuals respectively in 2006. If we apply Rai or Binet staging to the 1-year estimate, up to 45% of patients will be Stage III/IV or B/C and require immediate treatment. Thus 6,278 individuals may be treated within the first year of diagnosis. Of 55% (7673) under observation, by five years up to 33% (2,532) may have more advanced disease with increased risk of mortality.

Conclusion: While CLL is a rare disease, the number of individuals burdened by the disease within the EU is considerable and thousands of patients require treatment and physician care, which has cost implications for member states.
Imatinib Is Cost-Effective Comparing to Interferon-(IFN) for Patients with Newly Diagnosed Chronic-Phase (CP) Chronic Myeloid Leukemia (CML) from the Chinese Public Healthcare System Perspective.
Authors: Wang Chun , Chen Zi , Feng Weiwei
Published: October 2019

Background: Imatinib, a break-through oral molecular targeted therapy, has demonstrated impressive and durable responses as well as survival advantage compared to IFN based treatment in newly diagnosed CP CML (1, 2, 3). However, imatinib has not been registered on the Chinese National Reimbursement Drug List (RDL) whereas IFN has solely based on the drug price. Although IFN plus Ara-C has shown better efficacy than IFN alone, IFN is normally used alone to treat CP CML in China. The objective of this study was to conduct a cost-effective analysis comparing imatinib with IFN alone in newly diagnosed CP CML from the Chinese public healthcare systems perspective.

Methods: The 60-month data from the International Randomized Interferon versus STI571 Study (IRIS) was used to estimate survival for imatinib and utility values for survival. Since patients received IFN with Ara-C, and most patients randomized to receive IFN plus Ara-C crossed over to the alternate treatment imatinib in IRIS, historical data from the literature was used to estimate survival for IFN alone. Survival estimates were based on published survival curves for patients who achieved and those who did not achieve a complete cytogenetic response. Lifetime costs of treatment containing drug costs, office visits, lab tests, and hospitalizations were estimated based on treatment protocols from tier 3 hospitals in China. Incremental cost-effectiveness ratio (ICER), which is the difference in costs divided by the difference in quality adjusted life years (QALY) between imatinib and IFN, was calculated. All costs and outcomes were discounted at a rate of 3.5% per annum following the UK Health Technology Assessment recommendation.

Results: Total survival was estimated to be 19 and 9 for patients treated with imatinib and IFN, respectively. The discounted QALYs were 11.83 with imatinib and 5.41 with IFN. The discounted lifetime costs of treatment were RMB1169,661 with imatinib and RMB715,983 with IFN. The ICER for imatinib comparing with IFN was RMB70,510 per QALY.

Conclusion: The World Health Organization (WHO) considered a cost-effectiveness ratio (CER) of less than three times the GDP per capita as cost effective in developing countries (4). Based on the 2006 GDP per capita for China US$7,700 (5), the WHO CER for China would be RMB175,167. The ICER for imatinib over IFN was RMB70,510 which is less than half of the WHO CER threshold. Therefore, imatinib is cost-effective comparing with IFN in newly diagnosed CP CML from the Chinese public healthcare system’s perspective.
Day Hospital Approach to Uncomplicated Vaso-Occlusive Crises in Children with Sickle Cell Disease.
Authors: Raphael Jean L. , Kamdar Aditi , Mueller Brigitta U.
Published: October 2019

Day hospital management for patients with sickle cell disease experiencing uncomplicated vaso-occlusive pain crises has been described in adult populations as an alternative care delivery system. To date, there are no published studies addressing the utility of this model in pediatric populations. We retrospectively studied all admissions to the Day Hospital at the Texas Children’s Sickle Cell Center since its inception in 2000. A Day Hospital admission was defined as a minimum of two consecutive days of aggressive pain management as an outpatient, including intravenous hydration and analgesics, supported by home treatment over night with oral analgesic and anti-inflammatory agents. We gathered data on demographics, sickle cell genotype, incoming pain scale, provider type (physician versus nurse practitioner), home treatment with narcotics prior to presentation, average daily dose of narcotics administered during admission, length of stay, admission charges, return rate to the emergency department within 48 hrs, and transfer rate from Day Hospital to inpatient care. A total of 35 patients accounted for 80 visits during the study period (2000–2006). Approximately 83% of patients had sickle cell anemia (HbSS). The mean baseline hemoglobin for patients was 9.1 g/dl. Patients were seen equally by physicians and nurse practitioners. Approximately 93% of visits were preceded by home narcotic use within 24hrs of presentation. The mean incoming pain score was 7.9 on a scale from 1 to 10. The mean length of stay was 2.4 days. The return rate for emergency care within 48 hours was 6%. Approximately 40% of patients admitted to the Day Hospital were transferred to inpatient care for unresolved pain or increasing medical needs. We conclude that a dedicated Day Hospital facility has the potential to provide patient-centered, effective, and timely management of vaso-occlusive crises in children as well as adults. It may serve as an alternative to emergency and inpatient care for children with mild to moderate pain. Future studies should compare day hospital care to inpatient hospitalization for differences in length of stay, cost, patient satisfaction, and quality of life.
Long-Term Follow-Up of 132 Immunocompetent Primary Central Nervous System Lymphomas Treated at Leon Berard Cancer Centre: Proposition of a New Prognostic Model.
Authors: Ghesquieres Herve , Sunyach Marie Pierre , Drouet Youenn , Sebban Catherine , Chassagne Catherine , Jouanneau Emmanuel , Honnorat Jerome , Biron Pierre , Blay Jean-Yves
Published: October 2019

This study was aimed at analyzing long-term data on survival, relapse, and treatment-related neurotoxicity in all patients with newly diagnosed primary CNS lymphoma (PCNSL) and patients specifically treated with the C5R protocol (Blay et al, Blood86:2922,1995). We also identified prognostic factors of survival in order to propose a predictive model.132 patients with PCNSL seen at Leon Berard cancer centre between 1984 and 2006 were analyzed. Median age was 59 years (range: 26–81); 49% of the patients had a performance status (PS) of 2 to 4; 8% had leptomeningeal and ocular involvement. Initial treatment was chemotherapy and radiotherapy in 122 patients and chemotherapy alone in 10. Fifteen patients did not receive high-dose methotrexate as part of initial chemotherapy. The median overall (OS) and progression-free survival (PFS) for the whole series were 21.6 and 13.3 months for a median follow-up of 84.2 months. Twenty-five (19%) patients experienced toxic death, 24 (18%) progressed during treatment and 39 (30%) relapsed. Neurotoxicity was observed in 16% of the patients. Of the 49 patients receiving the intensive C5R protocol, 6 (12%) experienced toxic death, 3 (6%) progressed during treatment, 17 (35%) relapsed and 14% developed leukoencephalopathy. Median OS and PFS for patients treated with the C5R protocol were 73.8 and 44.4 months, respectively. Univariate analysis of the whole series showed that age over 60 years, elevated serum LDH, PS greater than 1 and the International Extranodal Lymphoma Study Group score were prognostic factors for OS and PFS, but not the presence of deep or multiple lesions or a high CSF protein level. The backward regression model integrating age, serum LDH, number and location of lesions, and CSF protein level showed that age, serum LDH and a tumor location within deep regions were predictive of OS and PFS. Four prognostic groups presenting 0, 1, 2 or 3 factors could be significantly distinguished regarding OS and PFS.

Overall Survival probability as a function of the number of risk factors among abnormal LDH, Age at diagnosis > 60 and deep lesion Overall Survival probability as a function of the number of risk factors among abnormal LDH, Age at diagnosis > 60 and deep lesion

This study allowed to identify a new prognostic model using 3 factors. This model has the interest to withdraw the PS which could be a subjective data and CSF protein level for which the accurate cutoff is not well known. This study also showed that, with a long follow-up, patients treated with the C5R protocol have excellent OS and PFS.
Pharmacologic Replacement of BIM BH3 Reactivates Apoptosis in Hematologic Cancer and Lymphoproliferative Disease.
Authors: LaBelle James L. , Fisher Jill K. , Katz Samuel G. , Bird Gregory H. , Lawrence Chelsea E. , Silverstein Amy M. , Walensky Loren D.
Published: October 2019

Selective targeting of deregulated apoptotic protein networks is a promising pharmacologic strategy for subverting diseases of unrestrained cellular survival, such as cancer. BCL-2 family protein interactions constitute a critical control point for the regulation of apoptosis. Whereas multidomain anti-apoptotic proteins such as BCL-2 guard against cell death, multidomain pro-apoptotic proteins such as BAX constitute a gateway to cell death through mitochondrial damage. The BH3-only proteins function as death sentinels situated throughout the cell, poised to transmit signals of cellular injury to multidomain members. BH3-only proteins deliver their death messages via their conserved alpha-helical BH3 domains. Whereas the indirect activator class of BH3-only proteins (e.g. BAD) counteract anti-apoptotic proteins, the direct activator subgroup (e.g. BIM) is believed to trigger apoptosis both by neutralizing anti-apoptotics and by directly activating the mitochondrial executioners BAX and BAK. The essential roles of BH3-only proteins in maintaining cellular homeostasis is highlighted by the development of autoimmune disease and cancer in mouse models of BH3-only protein deficiency. By inserting hydrocarbon “staples” into native BH3 peptide sequences, we have produced a chemical toolbox of stabilized alpha-helices of BCL-2 domains (SAHBs) to dissect apoptotic signaling pathways in vivo and explore the pharmacodynamic effects of “BH3 replacement” in cancer cells and mouse models of deregulated apoptosis. Whereas SAHBs display high affinity binding to anti-apoptotic targets, BID and BIM SAHBs also directly engage BAX and are thus especially potent in inducing apoptosis of a panel of leukemia and lymphoma cell lines. To evaluate the impact of selective BH3 replacement in vivo, we tested the capacity of BIM SAHB to reactivate apoptosis in the lymphoproliferative disease of Bim-/- mice. Strikingly, Bim-/- mice treated with BIM SAHB displayed marked influx of tingible-body macrophages into the lymphoid infiltrates of affected organs, with scattered cells throughout the infiltrate robustly positive for activated caspase-3, suggestive of SAHB induced apoptosis induction. Our studies highlight the therapeutic potential of BH3 replacement to circumvent apoptotic blockade and restore the death pathway in hematologic cancer and lymphoproliferative disease.
Gene Expression Profiling of Pulmonary Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma Identifies New Diagnostic Markers, Biological Heterogeneity and Therapeutic Targets.
Authors: Chng Wee J. , Fonseca Rafael , Bergsagel Peter Leif , Vrana Julia A. , Kurtin Paul J. , Remstein Ellen , Dogan Ahmet
Published: October 2019

To further understand the molecular biology of mucosa-associated lymphoid tissue (MALT) lymphoma, we conducted a comprehensive gene expression study on the Affymetrix platform using total RNA extracted from biopsy specimen of 35 well-characterized pulmonary MALT lymphoma samples and compared them to gene expression profiles of a range of B and T cell lymphoma, such as Burkitt’s lymphoma, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, multiple myeloma, and peripheral T-cell lymphoma, and normal cellular counterparts, such as different B-cell and T-cell populations, normal plasma cells and lung tussue. Analytical strategies were adopted to negate tissue specific effect such that our results can be generalized to MALT lymphoma from other anatomical sites. We further analyzed the data using functional tools such as gene-set enrichment analysis and gene ontology. Network/pathway analysis was performed using Metacore. Unsupervised clustering of whole dataset (including other lymphoid malignancies and normal cellular counterpart) using genes with variable expression, showed that compared to other B-cell lymphoid malignancies, MALT lymphoma have a prominent T-cell signature. Using established gene expression of different B-cell compartment, we confirmed that MALT has a marginal zone B-cell and memory B-cell cell-of-origin signature. Using ANOVA with post-hoc pair-wise comparison, we identified 4 novel transcripts over-expressed in MALT but not other B-cell tumors, and validated one of these using immunohistochemistry. MALT lymphoma with t(11;18) or t(14;18) over-expressed genes enriched for pathways other than the NFKB pathway such as JAK-STAT and SRC signaling pathways, which may represent novel therapeutic targets. We identified a number of genes with ‘outlier’ expression including RARA and RGS13. However, translocation involving RARA and the immunoglobulin heavy chain locus was not detected by FISH, suggesting other mechanisms of deregulating gene expression were involved. Using unsupervised clustering of only the MALT samples, we found that the molecular heterogeneity within MALT is composed of a group characterized by MALT1 translocations and another group with plasmacytic differentiation. Interestingly, further refinement of this grouping can be achieved by clustering the samples based on ‘outlier’ gene expression. Samples with MALT1 translocations have high expression of RARA, samples with plasmacytic differentiation have high FKBP11 expression and samples with high RGS13 expression tend to have trisomy 3 and reactive follicles. Our study therefore identified novel molecular markers, deregulated pathways and genetic defects in MALT. Furthermore, subgroups with distinct pathological features and anchored by unique pattern of ‘outlier’ gene expression were identified.
Evaluation of AMG 531 Efficacy in Nonsplenectomized Patients with Chronic Immune Thrombocytopenic Purpura (ITP) in a Randomized Placebo-Controlled Phase 3 Study.
Authors: Kuter David J. , Bussel James B. , Senecal Francis M. , Aledort Louis M. , Kessler Craig M. , Sanz Miguel A. , Liebman Howard A. , Slovick Frank T. , Kelly Reggie , Guo Matthew , Nichol Janet L.
Published: October 2019

AMG 531 is a novel platelet-stimulating peptibody that stimulates the thrombopoietin (TPO) receptor, and is being studied for its ability to increase production of platelets. Here we report efficacy data in nonsplenectomized patients from a randomized, double blind, placebo-controlled Phase 3 study designed to evaluate the efficacy and safety of AMG 531 in patients with chronic ITP. Sixty-two nonsplenectomized patients were enrolled (placebo, 21; AMG 531, 41) with a median age of 52 years (range 21 to 88) and a mean baseline platelet count of 18.3x109/L. Subcutaneous AMG 531 or placebo was administered weekly for 24 weeks at a starting dose of 1μg/kg, and adjusted to maintain a target platelet count of 50-200x109/L. One patient randomized to placebo received 3 doses of AMG 531 in error and was included in the efficacy analysis as a placebo. The primary study endpoint was the incidence of a durable platelet response, defined as a platelet count ≥50x109/L for ≥6 weeks during the last 8 weeks of the 24-week treatment period in the absence of rescue medications. Starting at a low dose of AMG 531 and gradually increasing it, as well as reducing the dose of steroids in certain patients, contributed to lower platelet counts early in the study. Twenty-five of the 41 patients (61.0%) receiving AMG 531 achieved a durable platelet response compared to 1/21 (4.8%) receiving placebo (p<0.0001). Overall response, defined as either durable or transient platelet response (≥4 weekly platelet responses), was observed in 36/41 (87.8%) patients receiving AMG 531, but was observed in only 3/21 (14.3%) placebo patients. The mean number of weekly platelet responses (platelet count ≥50x109/L) was significantly greater in patients receiving AMG 531 (15.2/24 weeks, 63%) compared to placebo (1.3/24 weeks, 5%) (p<0.0001). AMG 531 reduced the proportion of patients requiring ITP rescue medications, defined as either increase from baseline in dose of concurrent ITP medication or use of new medication to increase platelet counts. Thirteen of 21 (61.9%) placebo-treated patients received rescue medications compared to just 7/41 (17.1%) AMG 531-treated patients (p=0.0004). There were no treatment-related serious adverse events and no patients tested positive for neutralizing antibodies against either AMG 531 or endogenous TPO. In summary, as in previous studies, AMG 531 was well-tolerated while effectively increasing and sustaining platelet counts in nonsplenectomized patients with ITP. When compared to placebo, AMG 531 administration resulted in a higher mean platelet count, and was associated with less frequent use of rescue medications.
A Population (Registry) Based Analysis of the Impact of Bcr-Abl Specific Tyrosine Kinase Inhibition on Survival after Diagnosis of Philadelphia Chromosome Positive Chronic Myelogenous Leukemia..
Authors: Turner A. Robert , Hewitt Joanne D , Kamruzzaman Anmmd , Larratt Loree M. , Rusnak Deborah A. , Cox-Kennett Nanette , Belch Andrew R.
Published: October 2019

Specific tyrosine kinase inhibition (TKI) of the bcr-abl fusion protein in Philadelphia chromosome positive chronic myelogenous leukemia (CML) was introduced into general use in 2000 after a plenary abstract presentation to ASH in December 1999. Here we report the impact of the use of TKI on survival of all patients with CML in a total population based registry in the province of Alberta in Canada where BMT has been in use since 1980, α interferon +/− cytarabine since 1990 and TKI since 2000. All therapies have been fully funded by the public health care system in Alberta. Alberta’s population in 2000 was 2.97 million.

Prior to 2000, allogeneic stem cell transplant (BMT) was the only curative therapy available but its application was limited to a minority of patients with CML. Alpha interferon induced a cytogenetic remission in some CML and alpha interferon plus cytarabine prolonged survival in CML.

CML AML n 5 yr survival % BMT n 5 yr survival % BMT *59% of deaths occurred in the first year after diagnosis in the 2000–06 cohort 1980–89 303 40% NA 540 13% NA 1990–99 276 48% 25 692 15% 13 2000–06 216 83%* 8 680 25% 16 p<0.0001 p<0.0001

A 5 year survival for CML (1980–89) of 40% is consistent with published data. The 48% 5 year survival for CML (1990–99) reflects the benefit of interferon. The 5 year survival of acute myelogenous leukemia (AML) in Alberta is provided for comparison to reflect general improvement in care.

The proportion of AML patients who had a BMT did not significantly change while there was a significant reduction in numbers of CML transplanted in 2000–06. Transplant status did not significantly affect outcome in CML patients with 75% of non-BMT and 84% of BMT patients still alive at 5 years (p=0.08). In contrast, transplant status was statistically significant in AML, with 5 year survival of 49% in those treated with BMT, compared to 17% of those not transplanted (p<0.0001).

The results of this study show that TKI therapy (primarily imatinib) has had a major impact on the outcome of CML treatment in the province of Alberta. Long term survival, >80%, has been achieved and it appears that almost all of these patients can look forward to a normal life expectancy without the need for BMT.
Stem Cell Transplantation in Remission Improves Survival in Acute Myelogenous Leukemia Associated with FLT3 Mutations
Authors: Borthakur Gautam , de Lima Marcos , Kantarjian Hagop , Xiao Lianchun , de Padua Silva Leandro , Garcia-Manero Guillermo , Giralt Sergio , Ravandi-Kashani Farhad , Pierce Sherry , Champlin Richard
Published: October 2019

Background: Mutations in fms-like tyrosine kinase 3 are thought to be relevant to leukemogenesis. Two types of mutations are described; internal tandem duplication (ITD) in the juxtamembrane domain and point mutation within the activation loop of the tyrosine kinase domain (TKD), which mostly affects asparate 835 (D835). ITD mutation is present in 20–30% of patients with acute myelogenous leukemia (AML) and is associated with poor outcome (Yanada, M. et al. Leukemia. 2005 ;19:1345–9). The role of stem cell transplant (SCT) is not established in patients with AML and FLT3 mutation.

Patients and Method: 125 patients (59% male) with AML and FLT3 mutation treated at M.D. Anderson Cancer Center between the years 2003 to 2007 were included in this analysis of predictors for survival. Age, PS, WBC, platelet count, hemoglobin level, bilirubin, creatinine, albumin, beta 2 microglobulin (B2M), response (CR/CRp vs others), transplant recipient status (yes/no) were included in uni and multi-variate analysis.

Results: Seventy-seven percent patients had ITD mutation and fourteen patients (11%) had both ITD and D835 mutation. Median age was 59 years (range, 17–84), WBC count 17.3 x 106/ml (range, 1–300.5), platelet count 50 x 109/ml (range, 7–313) and hemoglobin 8.1 gm/dL (range, 4.2–13.9). Most (98%) had a performance status of 0–2 (median=1) and cytogenetic was diploid in 72%. All patients underwent cytarabine based induction chemotherapy.

Fifty-seven percent patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and induction related death rate was 9%. Eighty-six (69%) patients died and median overall survival (OS) was 10.4 months (95% CI of 7.62 to 14.08 months). There was no difference in OS between ITD mutation and D835 mutation. Twenty-seven patients (22%) underwent stem cell transplantation; 13 in CR1, 7 with bone marrow blast ≥ 10%). On univariate analysis transplant recipient status, PS, response, age, creatinine, albumin and B2M were significantly associated with OS. Patients who underwent transplant had a better OS (median = 15.7 months versus 7.6 months, p=.007) (Fig.1). On multi-variate analysis transplant recipient status, PS, ITD mutation and creatinine impacted OS. Age was a marginally significant predictor for OS.

Conclusion: Stem cell transplantation in CR/CRp appears to improve OS in patients with AML and FLT3 mutation. Results of trials incorporating FLT3 inhibitors into induction/consolidation regimens are eagerly awaited.

Fig.1: Survival by transplant status in patient with AML and FLT3 mutation Fig.1:. Survival by transplant status in patient with AML and FLT3 mutation
Impact of Comorbidity Index on Outcome with Allogeneic Hematopoetic Stem Cell Transplantation for Chronic Lymphocytic Leukemia
Authors: Toze Cynthia L. , Sangara Rauvynne N , Connors Joseph M. , Nevill Thomas J. , Shepherd John D. , Lavoie Julye , Barnett Michael J , Nantel Stephen H. , Voss Nicholas , Hogge Donna E. , Sutherland Heather J. , Forrest Donna L , Song Kevin W , Mourad Yasser Abou , Power Maryse M , Narayanan Sujaatha , Brinkman Ryan , Smith Clayton
Published: October 2019

Chronic lymphocytic leukemia, a disease that is not curable with standard therapy, is an attractive target for allogeneic (allo) hematopoetic stem cell transplant (HSCT) with demonstrated strong graft vs. leukemia effect. However, optimal selection of patients (pts) in order to maximize outcome and minimize toxicity is still under study. We hypothesized that patient co morbidity, as measured by the HSCT adapted Charlson co morbidity index (CCI) would have a strong effect in this group of patients with older median age. At the Leukemia/BMT Program of BC the CCI has been prospectively calculated for HSCT pts since 2006, and we performed chart review to calculate scores retrospectively for the remaining CLL allo HSCT patients in order to evaluate the impact of this factor on outcome following allo HSCT. Transplant specific data was collected prospectively and entered into an electronic database. Forty pts with CLL proceeded to allo HSCT between Jan 91 and Dec 07, with myeloablative (MA) (n=21) or non-myeloablative/reduced-intensity (NMA/RIC) (n=12/7) conditioning regimen. Median (range) number of prior therapies was 4 (1–7). Twenty-four pts were refractory to fludarabine. Donors were related in 25 cases, unrelated in 15. Median age (range) was 49 yrs (32–57) (MA) and 57 yrs (52–64) (NMA/RIC), with 3 and 13 patients greater than age 55 in the 2 groups respectively. Interval from dx to HSCT was 60 months (range 7–135) (MA) and 90 months (range 18–350) (NMA/RIC). Five yr OS is 55% for the whole group; 51% for the MA group at a median follow-up (med FU) of 7.2 yrs (range 2.8–14.6) and 62% for the NMA/RIC group with med FU of 4.2 yrs (range 0.1–6.8). OS did not differ between the 2 groups (p=0.56). Related and unrelated donors had similar 5yr OS at 60.6 vs. 47.1%, p=0.23. Cumulative incidence of non-relapse mortality at 100 days and 2 years is 10 and 32% for the whole group, 14 and 38% for the MA and 6 and 26% for the NMA/RIC groups. CCI was 0, 1, 2, and 3 or greater for 21, 5, 7, and 7 patients. OS by CCI 0–2 vs. >=3 was 63 vs.18% for the whole group (p=0.01), 56 vs. 0% for the MA (p=0.03), and 74 vs. 27% for the NMA/RIC groups (p=0.06). Further analyses will explore the relationship between CCI and NRM, acute and chronic graft vs. host disease, and relapse. Patient numbers in this series are insufficient to evaluate the impact of specific co morbidities. In conclusion, for patients with CLL, who are in general of older age, and who may have other therapeutic options, allo SCT is optimally performed in those with a low co morbidity score. Patients with a CCI of 3 or greater may be preferential candidates for alternate less toxic therapies.
Outcome of Allogeneic Stem Cell Transplantation in Patients with Low Ventricular Ejection Fraction
Authors: Khan Ziad U. , Saliba Rima M , Qureshi Suhail , Hosing Chitra , Giralt Sergio A , De Lima M. J , Yusuf S. W , Popat Uday R , Champlin Richard E , Qazilbash Muzaffar H.
Published: October 2019

BACKGROUND: High-dose therapy and Allogeneic stem cell transplantation (allo SCT) is a potentially curative treatment for patients with hematologic malignancies. A high risk of regimen-related toxicity limits this treatment only for patients with excellent organ-system function. A low left ventricular ejection fraction (LVEF) of ≤ 45% is considered to be a major risk factor for post-transplant cardiac toxicity and nonrelapse mortality (NRM). However, several patients with advanced hematologic malignancies and low LVEF can potentially benefit from this therapy. To address this issue, we evaluated the frequency of cardiac toxicity and NRM in 56 patients with low LVEF undergoing allo SCT.

METHODS: We performed a retrospective analysis on 56 patients with baseline low LVEF who received allo SCT between January 2000 and February 2006 at our institution. Pre-transplant evaluation included an electrocardiogram and bidimensional echocardiogram or gated cardiac scan. Cardiac toxicity was defined as congestive heart failure (CHF), atrial/ventricular arrhythmia or an acute coronary syndrome. Of the 56 patients, 22 received a myeloablative regimen (16 busulfan-based, 6 total body irradiation-based) while 34 patients received a fludarabine-based reduced intensity conditioning regimen.

RESULTS: Twenty-three patients (41%) received allo SCT from an unrelated donor. Acute leukemia was the reason for allo SCT in 32 (57%) patients. Baseline LVEF within 30 days pre-transplant ranged 20 to 45%. At their 6 month follow-up, cardiac toxicity was seen in 7 (12%) patients. Toxicity included congestive heart failure (CHF) in 4 (7%) and atrial fibrillation (AF) in 4 (7%). One patient had both CHF and AF. There were no documented episodes of acute coronary syndrome. Cumulative incidence of NRM at 100 days was 12%; none of the deaths were attributable to cardiac causes. These results were comparable to allo SCT performed in patients with normal LVEF. Variables such as age, LVEF, type of transplant, or the underlying disease did not emerge as significant predictors of post-transplant cardiac toxicity or NRM.

CONCLUSION: Patients with low LVEF (<45%) are acceptable candidates for allo SCT. A prospective study with stratification of cardiac risk factors is warranted in patients with low LVEF.
Identification of the JAK/STAT Signaling Pathway as a Valid Therapeutic Target of T(8;21) Acute Myeloid Leukemia Using Combined Gene Expression and Promoter Occupancy Profiling.
Authors: Lo Miao-Chia , Peterson Luke F. , Yan Ming , Ahn Eun-Young , Ommen Hans B. , Chen I-Ming , Hokland Peter , Willman Cheryl L. , Zhang Dong-Er
Published: October 2019

t(8;21) is one of the most common chromosomal abnormalities associated with acute myeloid leukemia (AML). The resulting AML1-ETO fusion protein is directly involved in the pathogenesis of AML but is not able to cause leukemia on its own. We have shown previously that a C-terminal splice variant of t(8;21), AML1-ETO9a (AE9a), is sufficient to promote AML in mice. Here we show that the leukemia-initiating cells reside in the Lin-/Sca1-/cKit+ population. To identify molecular targets directly modulated by AE9a, we compared the gene expression profile to the promoter occupancy (ChIP-on-chip) profile of this population. We identified 1485 genes deregulated by AE9a, among which 544 genes are also ChIP-on-chip targets. CD45, a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, was greatly down-regulated in AE9a leukemia cells. We further show that t(8;21) AML-M2 patient samples have lower CD45 levels compared to non-t(8;21) AML-M2 samples. Interestingly, JAK1 and JAK2 were upregulated by AE9a and both CD45 and JAK1 are ChIP-on-chip targets. In addition we show that JAK/STAT signaling was enhanced in the leukemia cells. Consequently, the leukemia cells are more susceptible to JAK2 inhibitors than wild type cells. Our results indicate that AE9a enhances JAK/STAT signaling by directly modulating regulators of this signaling pathway, which provides a potential novel approach to treating t(8;21) AML.
E2a-Pbx1 Direct Targets and Secondary Mutations in Leukemogenesis.
Authors: Diakos Christofer , Xiao Yuanyuan , Hofmann Jerry , Zheng Shichun , Kang Michelle , Zhou Mi , Wiencke John , Zhong Sheng L. , Wiemels Joseph L.
Published: October 2019

E2a-Pbx1 is expressed as a result of the t(1;19) chromosomal translocation in nearly 5% of cases of acute lymphoblastic leukemia. The E2a-Pbx1 chimeric transcription factor contains the N-terminal transactivation domain of E2A fused to the C-terminal DNAbinding homeodomain of Pbx1. Previews studies indicate that additional genetic events may be required for E2A-Pbx1-leukemic transformation, based on long incubation times and monoclonal nature of tumors observed in mouse models. While there is no doubt of its oncogenic potential, the mechanisms of E2a-Pbx1-mediated pre-B cell transformation and the nature of direct E2a-Pbx1 target genes and additional events that complement the fusion oncogene to create full-blown leukemia are still unclear. Herein we used chromatin immunoprecipitation (ChIP-chip) assays to identify direct targets of E2a-Pbx1, and we used gene and miRNA expression arrays of siRNA E2a-Pbx1-silenced cells to evaluate changes in expression induced by the fusion protein. To identify complementary genetic rearrangements, analyses of primary E2a-Pbx1 leukemias were performed to copy number changes and loss of heterozygosity which might identify mutations that synergize with the direct/functional E2a-Pbx1 targets to produce the leukemic phenotype. These arrays were analyzed in comparison to high-density gene promoter methylation arrays. Our data identified members of the WNT pathway as direct targets of E2a-Pbx1. Expression data from E2a-Pbx1 silenced cells support this finding as they demonstrate a functional regulation of this pathway. We further show a differential impact of E2a-Pbx1 silencing on the miRNA profile and identify E2a-Pbx1 dependent miRNAs. Using CGH arrays on primary E2a-Pbx1 samples we were able to pinpoint candidate secondary mutations as well as broad genetic categories: cases with 1q+, 1q+ combined with 9p-, and, separately, cases with +8. In summary we present direct and functional E2a-Pbx1 targets as well as candidate secondary mutations. We propose a model were direct and functional E2a- Pbx1 driven pathways that might include both genes and miRNAs might collaborate with identified auxiliary events to produce the E2a-Pbx1 leukemia.
A Poor Response to Desmopressin Is Observed in Patients with Mild Hemophilia a and No Detectable FVIII Mutation.
Authors: Castaman Giancarlo , Giacomelli Sofia , Santagostino Elena , Tosetto Alberto , Mancuso MariaElisa , Mannucci Pier M. , Rodeghiero Francesco
Published: October 2019

Background. Desmopressin is the treatment of choice for patients with mild hemophilia A (FVIII:C 3; 5 %). However, the range of response is wide and patients with similar basal FVIII:C may respond in a significantly different way. Several clinical studies have demonstrated the clinical efficacy and safety of desmopressin, but few data are available on the relationship of biological response with a given FVIII mutation and physiological characteristics (such as age and blood group, or von Willebrand factor levels). Aim of the study. To evaluate the relationship between type of FVIII mutation, physiological caharacteristics and response to desmopressin

Methods. The biological response to subcutaneous desmopressin was assessed in a group of 51 consecutive patients with FVIII:C 3 5%. Blood samples were taken at 0, 30, 60, 120 240, 480 minutes and 24 hours after injection. FVIII mutation search strategy was based on DHPLC and gene sequencing.

Results Mean basal FVIII:C was 18 ± 9 U/dL (range 5 – 37) and the median increase at peak was 2.5-fold (range 1.1 – 7.1). Twelve patients with low FVIII:C and normal or increased FVIII:Ag (type II defect) had similar basal and fold increase compared to the remaining patients. By multivariate regression, VWF:Ag peak level reached after desmopressin infusion and patient age were positively related with the FVIII:C half-life (p=0.003 and p=0.002 respectively), but not with FVIII:C peak or AUC. A total of 28 different gene mutations were identified (10 novel) in 42 patients, while 9 had no detectable gene mutations even after two different complete gene sequencing with 2 different sets of primers. No mutations in exons 18–22, 24 and 27 of VWF were identified. Patients with no mutations had similar basal median FVIII:C (15 vs 19 U/dL) and VWF:Ag levels (109.1 ± 31.7 vs 133.1 ± 57.5 U/dL) compared with patients carrying missense mutations. However, the peak of FVIII:C was significantly lower in patients without mutations (median FVIII:C 26 vs 56 U/dL; P < 0.001), with only a 2-fold increase (range 1.1 – 2.7) vs 2.92-fold (range 1.6 – 7.1) in patients with mutations (P < 0.001 by ANOVA).

Conclusions. A poor biological response to desmopressin was associated with the absence of an evident FVIII mutation.
Relevance of Chloride Binding to Von Willebrand Factor in Type 2B Von Willebrand Disease Patients.
Authors: Baronciani Luciano , Peyvandi Flora , Punzo Margherita , Canciani Maria T. , Di Stasio Enrico , Federici Augusto B. , Mannucci Pier M. , De Cristofaro Raimondo
Published: October 2019

Background: In von Willebrand disease type 2B (VWD2B) the abnormal VWF spontaneously binds to circulating platelets, usually resulting into loss of high molecular weight multimers (HMWM) and thrombocytopenia. In these patients VWF:RCo/Ag ratio is indicative of reduced HMWM and roughly correlated with the severity of VWD2B defect. Physiological concentrations of Chloride ions (Cl−) inhibit the hydrolysis of VWF by ADAMTS-13. Cl− acts as an allosteric effector and its specific binding to VWF A1 domain results into a reduced availability of A2 to be proteolised by ADAMTS-13. Type 2B VWF R1306W showed a reduced affinity to Cl− (>KdCl−) and an increased (>kcat/Km) susceptibility to proteolysis by ADAMTS13 (De Cristofaro, R. et al Molecular mapping of the chloride-binding site in VWF. J Biol Chem2007; 281: 30400–11).

Aim: To determine if other VWD2B mutations affect Cl– binding by changing the proteolysis of mutant VWF by ADAMTS-13.

Methods: Five distinct mutant recombinant (r)A1-A2-A3 proteins (Table), have been prepared along with the WT. Determination of KdCl− of each rA1- A2-A3 was achieved by intrinsic protein fluorescence, performed as a function of both Cl− concentrations and temperature. Study on the kinetic rates of hydrolysis of each rA1- A2-A3 by ADAMTS-13 was evaluated using HPLC methods.

Results and Conclusions: The results (Table) confirmed that affinity of Cl− (KdCl−) was decreased in all mutant rA1-A2-A3s compared to the WT at different extent, with an inverse correlation to the catalytic specificity (kcat/Km) of ADAMTS-13 interaction. Higher VWF:RCo/Ag ratios were found associated with lower values of kcat/Km in our studied patients. This finding strongly support that the reduced affinity of type 2B VWF to Cl− might contribute to the depletion of HMWM.

Table (patients) WT --- R1341Q (4) R1341W (3) H1268D (1) V1316M (4) R1306W (15) KdCl− (mM) 156 191 359 481 526 540 kcat/Km (M−1s−1) 7.25x104 8.8x104 1.2x105 1.39x105 1.6x105 1.95x105 VWF:RCo/Ag ratio (range) 0.7 – 1.2 0.8 (0.77–0.84) 0.7 (0.6–0,8) 0.5 0.3 (0.2–0.7) 0.5 (0.25–1.0)