Center Experience and Calendar Year Of Transplantation Strongly Influence Short Term Survival After Autologous Peripheral Blood Transplantation In 1315 Patients With Light Chain Amyloidosis: An EBMT Analysis

Abstract Introduction High-dose chemotherapy and autologous stem cell transplantation (ASCT) is a treatment option for eligible patients with systemic light chain (AL) amyloidosis. Compared to patients with multiple myeloma (MM), the risk for complications and transplant-related mortality is increased. However, in this fragile patient group it is often not possible to distinguish between treatment- and amyloidosis-related deaths in the post-transplant period. The CIBMTR reported a one year survival (1-yr OS) of 66% of patients transplanted between 1995 and 2001. Another multicenter analysis from Great Britain reported a one year survival of 75% (Goodman et al., BJH, 2006); interestingly, they could show a significant reduction of day 100 all-cause mortality from 32% to 13% after 1998. In recent single center studies 1-yr OS was better ranging from 80% to 90% (reviewed by Schönland et al., BMT, 2011). The amyloidosis groups of Mayo Clinic and Boston Medical School could also show a survival improvement over time (Tsai et al., Blood, 2012 and Gertz et al., BMT, 2010). Specific Aim The aim of this retrospective study was to analyze the 1-yr OS after ASCT for patients with AL amyloidosis in Europe. Of special interest were calendar year of transplants and center experience. Methodology Patient-, disease-, and transplant-related variables were collected according to the data entries in the EBMT database. Inclusion criteria were as follows: first autologous transplant with peripheral blood stem cells performed between 1997 and 2010. Center experience was measured for each patient by the number of previous MM ASCT done in the center until the year of AL transplant. Results 1315 patients from 259 centers fulfilled the entry criteria and were included in the analysis (for patient characteristics see table). The conditioning regimen was high-dose melphalan in most cases. Median follow up was 47 months. 1-yr OS after ASCT was 80.7% (CI 78.5 – 82.9). In univariate analysis age, gender, time from diagnosis to ASCT had no influence on 1-yr OS. Bad performance status (57% (50-65) vs. 90% (87-92); p<0.001) and progression/relapse as status at conditioning (61% (53-69) vs. 85% (83-87); p<0.001) significantly reduced 1-yr OS. A strong and significant influence of the transplant period (see figure 1, log-rank test, p<0.001) and higher center experience (see figure 2; log-rank test, p<0.001) could also be demonstrated. Interestingly, the proportion of patients with bad performance status decreased from 28% to 13% in most recent years (p=0.001). These results hold in multivariate analysis. Bad performance status (HR 4.3; p<0.001), progression/relapse as status at conditioning (HR 1.96; p<0.001) and earlier transplant period (HR 1.1; p<0.001) retained their highly significant negative influence on 1-yr OS. In an alternative multivariate model replacing transplant period with center experience, the latter has also a beneficial effect (HR 0.99 for 10 additional previous MM transplants; p=0.015) and all other prognostic factors retained the estimated effects. Conclusion This is the first report from the EBMT about the results of ASCT in AL amyloidosis from 259 European centers and the largest retrospective analysis for this rare entity. It clearly shows that short term survival has been improved over time probably due to better patient selection and increase of center experience. Of note, in the most recent cohort (2009 to 2010) the 1-yr OS was 91% (CI 87-96) supporting the further use of ASCT in eligible AL amyloidosis patients. Disclosures: Leblond: Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

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Treatment Choice and Outcome In Diffuse Large B Cell Lymphoma (DLBCL) Patients 75 Years and Older

Blood ◽

10.1182/blood.v116.21.733.733 ◽

2010 ◽

Vol 116 (21) ◽

pp. 733-733

Author(s):

Christiana E. Toomey ◽

Alona Muzikanksy ◽

Alfred Ian Lee ◽

Jeffrey A. Barnes ◽

James S. Michaelson ◽

...

Keyword(s):

Board Of Directors ◽

Charlson Comorbidity Index ◽

Performance Status ◽

B Cell Lymphoma ◽

Rank Test ◽

Very Elderly ◽

Advisory Committees ◽

Log Rank Test ◽

Comorbidity Index ◽

Ecog Ps

Abstract Abstract 733 Background: Previous studies have noted that advanced age may not predict survival in diffuse large B-cell lymphoma (DLBCL) when adjusted for health-related comorbidities. Very elderly patients over age 75, however, have been underrepresented in prior studies, so the interaction of prognostic factors in these patients treated with modern chemotherapy has not been assessed. According to SEER the median age at diagnosis of non-Hodgkin lymphoma in 2003–2007 was 67 years. Incidence is rising, with prevalence of diagnosis in men over 75 having increased almost threefold from the late 1970s. We sought to determine the impact of known prognostic factors and therapy choice in the very elderly. Methods: We used an IRB-approved clinicopathologic database to identify all patients 75 years of age and older with a diagnosis of DLBCL. Patients were excluded if they had primary lymphoma of the central nervous system. Since 1996, 154 patients over the age of 75 were diagnosed with DLBCL at MGH out of a total DLBCL population of 2097 patients in that period. Detailed chemotherapy information was available on 116 and are included in our analysis. The following information was collected: clinicopathologic diagnosis, diagnosis date, site of disease, age at diagnosis, vital status, and last known follow up. State and national sources were used to verify patient deaths. Information regarding prognostic status, number of extranodal disease sites, albumin, hemoglobin, and lactate dehydrogenase (LDH) was available for some patients. Charlson Comorbidity Index (CCI) was computed using ICD-9 codes. Age was assessed as a separate factor and not included in CCI computation. Severe toxicity to patients was determined by inpatient discharge summaries during their chemotherapy regimen. Likelihood that a toxic event occurred was estimated from the presence of a discharge summary within six months after date of diagnosis. Overall survival was calculated from date of initial diagnosis until date of last follow-up or date of death. Results: The series included 81 patients ages 75–79 and 73 patients 80 years and older. Among patients age 75–79, 43 were men and 38 were women, and among 80 and older, 25 were men and 48 were women. Advanced stage and limited stage were equivalent in frequency at 71 and 67 respectively. ECOG performance status (ECOG PS) was available in 77 patients of whom 41 were >=2 and 36 were <2. Toxicity requiring hospitalization was present in 42 of 136 patients (unknown for 18 patients). Among these toxicities, cardiac, lung, and infectious complications were the most likely. Toxicities were; 23.8% had an infection related hospital admission within six months of diagnosis, 16.7% had a cardiac admission and 14.3% a pulmonary admission. Most patients had comorbidities, with the median Charlson Comorbidity Index (CCI) being 5. Treatment regimen data was available for 116 patients. Anthracyclines were used in 53.2% of 154 patients and Rituximab was used in 39% of 154 patients. Prior to 1996 treatment data for many patients was missing. Median survival time was 10.6 months. In the subgroup of patient treated with both anthracycline and rituximab the median OS was only 13.6 months. US population data from 2007 (the conclusion of this study) estimates life expectancy for 75 at 11.7 years and for 80 and older at 8.8 years. Univariate factors analyzed included sex, Ann Arbor Stage, ECOG PS, Charlson comorbidity index, and age over 80. Of these, only PS <2 versus ≥2 (p=0.0533, Log-Rank test), and age over 80 (p=0.0010, Log-Rank test) were significant, while limited/advanced stage, CCI were not. Chemotherapy was also evaluated in a univariate analysis. Use of anthracycline (present or absent in therapy) and rituximab use (present or absent) were both determined to confer a significant benefit to patient survival (respectively p=0.0055 and p=0.0106, Log-Rank test). Conclusions: Despite the use of intensive modern chemotherapy regimens the outcome of DLBCL in very elderly patients is poor with a median overall survival of approximately 1 year. Univariate predictors of outcome include age and performance status as well as the use of anthracyclines and rituximab. Over 30% of these patients will be admitted for treatment related toxicities. Novel therapeutic strategies are needed in this rapidly expanding demographic group. Disclosures: Hochberg: Giogen Idec: Speakers Bureau; Genentech BioOncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Enzon Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; WordCare: Membership on an entity's Board of Directors or advisory committees.

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Bioinformatics Analysis of The Expression of ATP Binding Cassette Transporters and The Screening of Regulatory Genes in PTEN/PI3K/Akt/mTOR Signaling Pathway in The Hepatocellular Carcinoma

10.21203/rs.3.rs-674099/v1 ◽

2021 ◽

Author(s):

Tingdan Zheng ◽

Wuqi Song ◽

Aiying Yang

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Overall Survival ◽

Bioinformatics Analysis ◽

Wilcoxon Test ◽

Rank Test ◽

Short Term ◽

Term Survival ◽

Log Rank Test ◽

Short Term Survival

Abstract Objective Here we performed the Bioinformatics analysis on the data from The Cancer Genome Atlas (TCGA), in order to find the correlation between the expression of ATP Binding Cassette (ABC) Transporters’ genes and hepatocellular carcinoma (HCC) prognosis; Methods Transcriptome profiles and clinical data of HCC were obtained from TCGA database. Package edgeR was used to analyze differential gene expression. Patients were divided into low-ABC expression and high-ABC expression groups based on the median expression level of ABC genes in cancer. The overall survival and short-term survival (n= 341) of the two groups was analyzed using the log-rank test and Wilcoxon test; Results We found that ABC gene expression was correlated with the expression of PIK3C2B (p<0.001, ABCC1: r=0.27; ABCC10: r=0.57; ABCC4: r=0.20; ABCC5: r=0.28; ABCB9: r=0.17; ABCD1: r=0.21). All patients with low-ABC expression showed significantly increased overall survival. Significantly decreased overall survival (Log-rank test: p<0.05, Wilcoxon test: p<0.05) was found in patients with high expression of ABCC1 (HR=1.58), ABCD1 (HR=1.45), ABCC4 (HR=1.56), and ABCC5 (HR=1.64), while decreased short-term survival (Log-rank test: p>0.05, Wilcoxon test: p<0.05) was correlated with the increased expression of ABCC10 (HR=1.29), PIK3C2B (HR=1.29) and ABCB9 (HR=1.23); Conclusions Our findings indicate that the specific ABC gene expression correlates with the prognosis of HCC. Therefore, ABC expression profile could be a potential indicator for HCC patients.

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Impact Of The Proportion Of Metaphases With Isolated Del(5q) On Clinical Outcomes In Lenalidomide (LEN)-Treated Patients With IPSS Low-/Int-1-Risk Myelodysplastic Syndromes (MDS) In MDS-003 and MDS-004

Blood ◽

10.1182/blood.v122.21.1538.1538 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1538-1538

Author(s):

Aristoteles Giagounidis ◽

Alan List ◽

Eva Hellström-Lindberg ◽

Mikkael A. Sekeres ◽

Ghulam J. Mufti ◽

...

Keyword(s):

Board Of Directors ◽

Clinical Outcomes ◽

Research Funding ◽

Rank Test ◽

Employment Equity ◽

Advisory Committees ◽

Log Rank Test ◽

Equity Ownership ◽

Baseline Characteristics ◽

Rbc Transfusion

Abstract Introduction The proportion of aberrant metaphases is prognostic for overall survival (OS) in MDS patients with trisomy 8 (Mallo M, et al. Leuk Res. 2011;35:834-6). The impact of the proportion of metaphases with del(5q) on clinical outcomes, including OS, disease progression and response to therapy with LEN in MDS remains undefined. In two large multicenter studies of LEN (MDS-003 and MDS-004) in RBC transfusion-dependent patients with International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk del(5q) MDS, RBC transfusion independence (TI) ≥ 8 weeks was achieved in 51–67% of patients (List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). This retrospective analysis evaluated response to treatment, progression to acute myeloid leukemia (AML) and OS by proportion of del(5q) metaphases in patients with isolated del(5q) from the MDS-003 and 004 studies. Methods In order to allow sufficient patient numbers for analysis, ≥ 16 metaphases were evaluated for del(5q) by standard karyotyping (MDS-003 and MDS-004) and 200 interphase nuclei were evaluated by fluorescence in situ hybridization (FISH; MDS-004 only) using a probe for the commonly deleted region 5q31 (LSI EGR1/D5S721, Abbott, Wiesbaden, Germany). Patients received LEN on days 1–21 of each 28-day cycle (10 mg) or continuously (5 mg or 10 mg), or placebo. In MDS-004, patients randomized to placebo could cross over to LEN 5 mg by week 16. RBC-TI ≥ 26 weeks, time to AML progression and OS were analyzed by the proportion of del(5q) metaphases or interphases (≤ 60% vs > 60%) using standard karyotyping and FISH, respectively. Results Of the 353 patients from MDS-003 and MDS-004, 194 had isolated del(5q) by standard karyotyping; median proportion of del(5q) metaphases was 96% (range 4–100). Baseline characteristics including age, time from diagnosis, RBC transfusion burden, hemoglobin level, platelet and absolute neutrophil counts were comparable among patients with ≤ 60% (n = 21) and > 60% (n = 173) del(5q) metaphases. Rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 0.6515). Time to AML progression was comparable for patients in the ≤ 60% group versus the > 60% group (log-rank test P = 0.9802); 2-year rates were 22.2% (95% confidence interval [CI]: 7.7–54.5%) and 14.6% (95% CI: 9.9–21.2%), respectively. Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.5514). OS was longer in the > 60% versus the ≤ 60% group (log-rank test P = 0.0436); median OS was 3.7 years (95% CI: 3.0–4.2) and 2.4 years (95% CI: 1.5–4.9), respectively. In MDS-004, the proportion of del(5q) interphases was analyzed using FISH in 106 patients, including 46 with ≤ 60% and 60 with > 60%. When analyzed by FISH, rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 1.000). Time to AML progression and OS were similar across these groups (log-rank test P = 0.7311 and P = 0.8639, respectively) when analyzed by FISH. In the ≤ 60% and > 60% groups respectively, 2-year AML progression rates were 14.8% (95% CI: 6.9–30.1%) and 18.6% (95% CI: 10.4–32.0%), and median OS was 3.1 years (95% CI: 2.3–4.8) and 2.9 years (95% CI: 2.3–4.4). Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.8631). Conclusions In IPSS Low- or Int-1-risk MDS patients with isolated del(5q) treated with LEN in MDS-003 and MDS-004 studies, baseline characteristics, RBC-TI ≥ 26 weeks and AML progression were comparable in patients with > 60% versus ≤ 60% del(5q) metaphases. Although similar across groups when analyzed by FISH in a subset of patients, surprisingly, OS was longer in patients with > 60% del(5q) metaphases than in those with ≤ 60% del(5q) metaphases by standard karyotyping. However, the number of patients with ≤ 60% del(5q) metaphases was limited and no adjustment was made for multiple testing. These findings suggest that the number of cells with the isolated del(5q) abnormality measured by FISH does not impact clinical outcome in this RBC transfusion-dependent study population, but this finding could not be confirmed for OS by standard karyotyping. Disclosures: Giagounidis: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. List:Celgene: Serve on Celgene Data Safety & Monitoring Committee Other. Hellström-Lindberg:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Sekeres:Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Mufti:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schlegelberger:Celgene: Consultancy. Morrill:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Fenaux:Celgene: Honoraria.

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The Characterization Of Adrenal Insufficiency and Identification Of Its Risk Factors In Patients With Plasma Cell Dyscrasias

Blood ◽

10.1182/blood.v122.21.5376.5376 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5376-5376

Author(s):

Nadim K Choudhury ◽

Alice Levine ◽

Ajai Chari

Keyword(s):

Board Of Directors ◽

Serum Cortisol ◽

High Dose ◽

Al Amyloidosis ◽

Cortisol Response ◽

Inclusion Criteria ◽

Acth Stimulation Test ◽

Acth Stimulation ◽

Advisory Committees ◽

Al Amyloid

Abstract Background The introduction of proteasome inhibitors and immunomodulatory agents to treat patients with multiple myeloma (MM) and AL amyloidosis have greatly improved survival in these patients and allowed for the use of relatively steroid-sparing regimens. However, 40 mg of dexamethasone is still more than 50 times basal glucocorticoid secretion. Therefore, intermittent dosing of dexamethasone, the longest acting oral corticosteroid, while beneficial in terms of reducing side effects from chronic glucocorticoid excess, may still compromise endogenous adrenal gland function. Our hypothesis was that prolonged, intermittent use of high dose steroids can result in adrenal insufficiency in some patients. The aim of this retrospective study was to determine the characteristics of patients who developed AI. Methods Inclusion criteria for this retrospective case series were patients who had plasma cell disorders and who had been diagnosed with AI based on symptoms concordant with a low serum cortisol level (normal 6.7 - 22.6 mcg/dL), an inadequate cortisol response on an ACTH stimulation test, or for those patients with a fulminant clinical presentation - a rapid clinical improvement upon initiation of low dose maintenance corticosteroid replacement therapy. Exclusion criteria were patients who had serum cortisol levels checked in the setting of recent administration of corticosteroids, who had an adequate cortisol response to an ACTH stimulation test in the setting of a normal basal cortisol level, or who did not require replacement therapy to achieve resolution of symptoms. Results Sixteen patients met the inclusion criteria over a span of approximately 18 months. Two patients had AL amyloidosis, 12 had MM, and 2 had both. 3 patients were excluded. The median age of patients at the time of AI diagnosis was 61.5 (Range: 44-76). The median number of steroid-containing cycles taken before the diagnosis of AI was 10.5 (Range: 4-50) over a median of 27 months (Range: 3-129). The median cumulative steroid consumption was 1000 mg of dexamethasone. Of note, the 2 primary AL amyloid patients only received 4 and 8 cycles of corticosteroids and a lower amount of cumulative corticosteroids, 768 and 800 mg, respectively prior to being diagnosed with AI. The symptoms and signs of AI at the time of diagnosis included fatigue (88% of patients), diarrhea (56%), hypotension (56%), orthostasis (44%) and weight loss (31%). Other symptoms that appeared in multiple patients included nausea, diffuse myalgia, fever, and cardiovascular shock. The median time between the last steroid dose and the serum cortisol assay was 7 days (Range: 1-62), which resulted in a median serum cortisol of 3.7 mcg/dL (Range 0.5-21 mcg/dL). Of the seven patients who had serum ACTH levels checked, only one patient (with primarly AL amyloid) had an elevated ACTH of 68 (normal 12-46 pg/mL), suggesting a possible component of primary AI. Five patients also underwent ACTH stimulation tests, two of which demonstrated an inappropriate response, defined as a lower rise in serum cortisol than expected. To treat AI, patients received about 15-20 mg of hydrocortisone (equivalent to 0.6- 0.8 mg of dexamethasone) on days not receiving steroids for treatment of their malignancy. 2 patients requiring pressors for shock also required stress dose steroids. For patients with AI symptoms, normalization of hypotension and weight required a median of 9 days (Range 2-43 days) and 2 months (Range 0.3-20 months) respectively to return to their pre-AI levels. Orthostasis resolved after a median of 33 days (Range: 22-72 days), however, orthostatics were not checked at each clinic visit. Conclusions Our study shows that chronic treatment with even intermittent high-dose steroids can lead to AI, typically characterized by such nonspecific symptoms as fatigue, diarrhea, and dizziness occurring 3-4 days after the last exogenous steroid administration. Unfortunately, the debilitating presentation of some patients with orthostasis/hypotension as well as an already demanding schedule for chemotherapy visits makes optimal cortisol and ACTH stimulation testing challenging. A high index of suspicion for AI is required to initiate diagnostic and therapeutic interventions in a timely fashion to minimize the morbidity and mortality of this condition. Disclosures: Chari: Millenium : Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees.

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Busulfan/Fludarabine- or Treosulfan/Fludarabine-Based Conditioning Regimen in Patients with Wiskott-Aldrich Syndrome Given Allogeneic Hematopoietic Cell Transplantation — an EBMT Inborn Errors Working Party and Scetide Retrospective Analysis

Blood ◽

10.1182/blood-2018-99-112394 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2175-2175 ◽

Cited By ~ 2

Author(s):

Michael H. Albert ◽

Mary Slatter ◽

Andrew Gennery ◽

Tayfun Guengoer ◽

Henric-Jan Blok ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Rank Test ◽

Unrelated Donor ◽

Advisory Committees ◽

Secondary Procedure ◽

Log Rank Test ◽

Secondary Procedures

Abstract PV and AL contributed equally Multiple studies from the EBMT registry and others have shown excellent survival rates after allogeneic haematopoietic stem cell transplantation (HSCT)for Wiskott-Aldrich syndrome (WAS) patients (Ozsahin et al, Blood 2008). The importance of myeloid engraftment for full disease correction has also been demonstrated (Moratto et al, Blood 2011). However, the vast majority of HSCTs in these studies were performed with (oral) busulfan/cyclophosphamide-based conditioning and in the early 2000 years or before. In 2005, the inborn errors working party (IEWP) of EBMT and ESID first recommended busulfan/fludarabine (BuFlu) or treosulfan/fludarabine (TreoFlu) based conditioning for primary immunodeficiencies such as WAS, with some centers deciding to add thiotepa (TT) to the conditioning. We performed a retrospective analysis via the EBMT and SCETIDE registries of WAS patients transplanted between 01/01/20006 and 12/31/2016 with these two regimens. The primary objective was to compare the overall (OS) and event-free survival (EFS) after HSCT with either BuFlu±TT or TreoFlu±TT conditioning. Secondary objectives included the influence of either conditioning regimen on acute and chronic GVHD, the degree of donor chimerism, incidence of secondary procedures after HSCT (2nd HSCT, stem cell boost, DLI, gene therapy or splenectomy) and rates of disease-specific complications after HSCT. At the time of this interim analysis, 174 patients were included, 92 (53%) with BuFlu±TT and 82 (47%) with TreoFlu±TT conditioning with a median age of 1.57 years (range 0.21-29.96) at HSCT and a median follow-up of 32.9 months (range 1.5-128.9). The donor was an HLA-matched sibling (MSD) in 30, a matched related donor (MRD) in 5, a matched unrelated donor (MUD, 9/10 or 10/10) in 105, a mismatched unrelated donor (MMUD, <9/10) in 9 and a mismatched family donor (MMFD) in 25 (18 with ex-vivo T-cell depletion). Stem cell source was bone marrow in 93 (53%), peripheral blood in 62 (36%) and cord blood in 18 (10%). Two year overall survival (OS) of the entire cohort was 88.6% (95% confidence interval 83.5%-93.6%). There was no significant difference in OS between patients treated with BuFlu±TT or TreoFlu±TT conditioning (2-year OS 88.1% vs. 89.5%; log-rank test p=0.7). Patients aged >5 years had a worse OS as compared to those 5 years or younger at HSCT (74.9% vs. 90.8%; log-rank test p=0.005). The type of donor had no influence on OS: 96.4% for MSD/MFD, 86.8% for MUD/MMUD and 87.7% for MMFD (log-rank test p=0.4). Whole blood chimerism was complete (>90% donor) in 60/75 evaluable patients (80%) at last follow-up or before secondary procedure (if a patient had one), 39/40 (98%) in the BuFlu±TT group and 21/35 (60%) in the TreoFlu±TT group. Twenty-six patients required a secondary procedure: stem cell boost in 4 patients, donor lymphocyte infusion in 9, 2nd HSCT in 15 and splenectomy in 1. Twenty-two of these 26 (84.6%) are alive and 14 of 16 with available chimerism data have a complete donor chimerism (>90%donor) at last follow-up. The 2-year cumulative incidence (CI) of secondary procedures was higher at 33.9% in the TreoFlu±TT versus 12.8% in the BuFlu±TT group (Gray's test p=0.017), and 2-year EFS (secondary procedure or death as event) was 61.4% in the TreoFlu±TT and 75.0% in the BuFlu±TT group (log-rank test p=0.2). Grade II-IV acute GVHD had the same incidence in both groups (100 day CI 24.4% vs. 26.3%; Gray's test p=0.849) and chronic GVHD of any grade was borderline more frequent in the TreoFlu±TT group (2 year CI 17.2% vs 6.7%; Gray's test p=0.054). The cumulative incidence of disease-specific complications occurring more than 6 months post HSCT (severe infections, bleeding, autoimmunity) was not different between the two groups (6.5% vs. 6.4%; Gray's test p=0.92). There was no malignancy reported after HSCT except for one EBV-post-transplant lymphoproliferative disorder (PTLD) 2.7 months after HSCT. In summary, HSCT with either BuFlu±TT or TreoFlu±TT conditioning reliably cures almost 90% of patients with WAS regardless of donor type. WAS-related complications are very rare events more than 6 months post HSCT. More patients required secondary procedures after treosulfan-based than busulfan-based conditioning. These data confirm the feasibility and efficacy of the regimens currently recommended by the IEWP. Disclosures Slatter: Medac: Other: Travel assistance. Chiesa:Gilead: Consultancy; Bluebird Bio: Consultancy. Kalwak:Sanofi: Other: travel grants; medac: Other: travel grants. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria.

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Neutropenia in Children Treated with Deferiprone or Deferasirox: A Report of the Largest Randomized Trial of Oral Chelators in Transfusion-Dependent Pediatric Patients

Blood ◽

10.1182/blood-2019-127933 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3552-3552

Author(s):

Fernando Tricta ◽

Mariagrazia Felisi ◽

Oscar Della Pasqua ◽

Amal El-Beshlawy ◽

Hoda Hassab ◽

...

Keyword(s):

Board Of Directors ◽

Neutrophil Count ◽

Severe Neutropenia ◽

Rank Test ◽

Cumulative Hazard ◽

Advisory Committees ◽

Treatment Groups ◽

Log Rank Test ◽

Kaplan Meier ◽

Oral Chelators

Introduction: Agranulocytosis/severe neutropenia is an established adverse event during deferiprone (DFP) use. Less is known about milder episodes, which are frequently transient despite continuous deferiprone use. To provide further insight into this topic, we compared the incidence of neutropenia during DFP or deferasirox (DFX) treatment in the randomized Deferiprone Evaluation in Paediatrics (DEEP-2) trial, where blood neutrophil count was regularly monitored in patients randomized to be treated with DFP or DFX. Methods: DEEP-2 was a multicenter, randomized, 12-month, open-label trial comparing DFP vs DFX in pediatric (<18 years old) patients with transfusion-dependent hemoglobinopathies. 390 patients from 22 centers in 7 countries were randomized (1:1 DFP:DFX) and received at least one dose of the study medication (193 on DFP and 197 on DFX). Neutrophil count was regularly assessed every 7 +/-7 days in all patients. Neutrophil counts <500/mm3 were classified as agranulocytosis/severe neutropenia, 500 - <1,000 /mm3 as moderate neutropenia, and 1,000 - <1,500 /mm3 as mild neutropenia. The incidence of neutrophil counts below the threshold of neutropenia (1,500/mm3) and the rate of reported episodes of neutropenia as identified by the treating physician were compared between the two treatments. An ANOVA model was used to compare the time to neutropenia and time for its resolution between the two treatment groups. To compare the cumulative hazard curves was used the Kaplan-Meier log rank test. Results: 3579 and 4027 neutrophil counts were available for DFP- and DFX-treated patients, respectively. 47 (1.3%) of the total counts in 24 (12.4%) of the 193 DFP-treated patients versus 48 (1.2%) of the total counts in 27 (13.7%) of the 197 DFX-treated patients were below 1,500/mm3. Of these, 28 cases in 23 DFP-treated patients and 15 cases in 11 DFX-treated patients were reported by the treating physician as neutropenia, corresponding to a global incidence rate 11.9% for DFP and 5.6% for DFX (p=0.081, Chi-Square test). 23 (82.1%) of the 28 episodes of neutropenia during DFP use were considered drug related vs 2 (13.3%) of the 15 episodes during DFX use (p-value < 0.001, Fisher Exact test) (table 1). The mean (SD) treatment duration with either DFP or DFX prior to diagnosis of mild or moderated neutropenia was 127 (96.1) days and 101 (85.7) respectively. All those episodes, except for 2, resolved within a mean time of 13 days (1 - 42 days) in DFP-treated patients and 18 days (6 - 46 days) in DFX-treated patients. The 2 cases where neutropenia did not resolve were diagnosed as constitutional neutropenia and bone marrow suppression. There was no significant difference in those results between the two treatment groups as assessed by one-way ANOVA(p = 0.379), Log-Rank test (p = 0.065) or cumulative-hazard and Kaplan-Meier. During the study 3 events of agranulocytosis occurred, all in patients treated with DFP and not included in the present analysis. All 3 episodes resolved. Conclusion: Data from the largest randomized trial of oral chelators in transfusion-dependent pediatric patients provide evidence that, a drop in the neutrophil count below the threshold for mild neutropenia is very common (>10% of patients) for both DFP and DFX treated patients. All episodes of neutropenia, except for 2 with specific etiology, resolved, irrespective of their severity and of chelator used. A causal relationship of neutropenia to chelator use varied based on the chelator; the majority of events observed during DFP use were assessed by the clinician as drug related, whereas the majority of events observed during DFX use were assessed unrelated to its use. These data indicate that while agranulocytosis rate in DFP patients is not changed from previous reports, moderate/mild neutropenia represent discrete events in patients undergoing oral iron chelation therapy. Disclosures Tricta: ApoPharma: Employment. Della Pasqua:GlaxoSmithKline: Employment. Kattamis:Ionis: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees; Apopharma: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Reggiardo:CVBF: Consultancy. Spino:ApoPharma: Employment. Tsang:Apotex Inc.: Employment.

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Successful Treatment of AL Amyloidosis Patients over Age 65 with High-Dose Melphalan and Autologous Stem Cell Transplantation (HDM/SCT).

Blood ◽

10.1182/blood.v104.11.923.923 ◽

2004 ◽

Vol 104 (11) ◽

pp. 923-923

Author(s):

David Cary Seldin ◽

Jennifer J. Anderson ◽

Martha Skinner ◽

Karim Malek ◽

Daniel G. Wright ◽

...

Keyword(s):

Stem Cell ◽

Performance Status ◽

Treatment Protocol ◽

Complete Response ◽

Median Number ◽

Rank Test ◽

High Dose ◽

Al Amyloidosis ◽

Younger Patients ◽

Related Mortality

Abstract Over the past 10 years, HDM/SCT has been employed for treatment of patients with AL amyloidosis. Although peri-transplant mortality is greater than for other hematologic diseases, HDM/SCT leads to durable hematologic complete responses (CR), improvements in organ function, and extended survival in a substantial proportion of patients (Skinner et al., Ann. Int. Med. 2004). In that study, the proportion of patients eligible for HDM/SCT was lower for patients >65 years of age than for younger patients (34.3% vs. 68.4%), but the hematologic complete response (CR) rate and survival appeared to be no different. Here, we update these results and present a detailed analysis of outcomes in patients >65 vs. those <65. Data were collected with IRB approval. Through 07/01/04, 349 patients began G-CSF mobilization, of which 66 (19%) were >65. The median age of the 66 patients was 68, range 65–80; 73% male; 18% ? and 82% ?, while for the 283 patients <65, the median age was 55, range 29–64; 57% male; 16% ? and 84% ?. The median number of involved organs was no different in the two groups, nor was the type of organ involvement or performance status. There was also no difference in the rate of serious complications during stem cell collection, as a similar fraction of patients in both groups did not proceed to transplant, 12.1% of patients >65 versus 10.3% of patients <65 (p=.659). Based on treatment protocol, only 19% of patients >65 received an IV dose of melphalan of 200 mg/m2 (the remainder being treated with 140 mg/m2 or less), vs. 64% of those <65 (p <.001). There was no difference in early transplant-related mortality (10.3% in patients >65 vs. 13.4% in patients <65, p=.665). There was also no difference in one year mortality (22.4% for those >65 vs. 20.9% for those <65, p=.859). There was a non-significant trend towards a lower rate of hematologic CR in the older patients (32% vs. 44%, p=0.155). However, the median survival after HDM/SCT was no different (see fig; 4.9 years for patients >65 vs. 4.6 years for those <65, p=0.42 by log-rank test). Thus, while fewer patients >65 meet eligibility requirements for HDM/SCT, for those who do, treatment-related mortality, hematologic CR rate, and survival are no different than for younger patients. These data strongly support the use of HDM/SCT for suitable patients with AL amyloidosis who are >65 years old. Figure. Figure.

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Results of a Phase I-II Clinical Trial of Oxaliplatin, Fludarabine, Cytarabine, and Rituximab (OFAR) Combination Therapy In Patients with Aggressive, Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) and Richter Syndrome (RS)

Blood ◽

10.1182/blood.v116.21.923.923 ◽

2010 ◽

Vol 116 (21) ◽

pp. 923-923 ◽

Cited By ~ 2

Author(s):

Apostolia Maria Tsimberidou ◽

William G. Wierda ◽

Sijin Wen ◽

William Plunkett ◽

Susan O'Brien ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Clinical Outcomes ◽

Median Survival ◽

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Rank Test ◽

Advisory Committees ◽

Log Rank Test

Abstract Abstract 923 Background: To enhance the response rate with a decrease in myelosuppression that were observed with oxaliplatin, fluradabine, Ara-C, and rituximab (OFAR1) (Tsimberidou et al, J Clin Oncol, 2008;26:196), the daily dose of oxaliplatin was increased from 25 to 30mg, the daily dose of Ara-C was decreased from 1 g/m2 to 0.5 g/m2 and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods: OFAR2 consisted of oxaliplatin 30mg/m2 D1-4; fludarabine 30mg/m2; Ara-C 0.5g/m2; rituximab 375mg/m2 D3; and pelfigrastim 6mg D6. Fludarabine and Ara-C were given on D2-3 (level 1) D2-4 (level 2) or D2-5 (level 3) every 4 weeks. Tumor lysis, DNA virus, and PCP prophylaxis was administered. A “3+3” design was used (Phase I) and and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results: Overall 102 patients (rel. CLL 67, RS 35) were treated. Twelve patients were treated in the Phase I portion of the study. Dose-limiting toxicities were noted in 2/3 patients at level 3 (G4 diarrhea and G4 sepsis). Level 2 was the maximum tolerated dose. Ninety patients (CLL, 60; RS, 30) were treated in Phase II portion of the study (age > 60 years 67%, 17p del 37.5%, 11q del 15%, 13q del 18%, +12, 17%; neg. 12.5%; unmutated IgVH 81.5%, ZAP70-positive 77%, and CD38 30%, 63%). Response in 80 of 90 patients (Phase II) is shown in Table (too early, n=10). The overall response rates in patients (Phase II) with 17p deletion and 11q deletion were 29% and 41%, respectively. Twenty-nine patients underwent SCT after OFAR2 (response status to OFAR2 at the time of SCT: CR, n=3; nPR, n=2; 15; no response, n=9). With a median follow-up of 20.8 months, the median survival was 19 months (95% CI, 13–37+) and the median FFS was 6 months (95% CI, 3.4 – 8.2). Overall, 238 cycles were administered. G3-4 neutropenia, thrombocytopenia, and anemia were noted in 67%, 74%, and 44% of patients (51%, 64%, and 25% of cycles); and G3-4 infections in 19% of patients. Clinical outcomes of OFAR2 were compared with those of OFAR1. In patients with RS, the overall response rate was 41% (11/27) with OFAR2 and 50% (10/20) with OFAR1 (p = 0.57, Fisher's test); the median survival with OFAR2 and OFAR1 was 8.3 months and 18+ months, respectively (p = 0.92, log-rank test); and the respective median FFS was 3.0 months and 4.1 months (p = 0.40, log-rank test). In patients with CLL, the overall response rate was 55% (29/53) with OFAR2 and 33% (10/30) with OFAR1 (p = 0.36, Fisher's test); the median survival with OFAR2 was 21.4 months and 13.8 months with OFAR1 (p = 0.19, log-rank test); and the respective median FFS was 6.6 months and 4.9 months (p = 0.69, log-rank test). Conclusion: OFAR2 induced response in 41% of patients with RS and 55% of patients with relapsed/refractory CLL in the phase II study. Antileukemic activity was also noted in patients with 17p deletion. Although the numbers of patients are small, OFAR1 was associated with a trend towards superior clinical outcomes in patients with RS compared to OFAR2; and OFAR2 was associated with a trend towards superior clinical outcomes compared to OFAR1 in patients with relapsed/refractory CLL. Disclosures: Tsimberidou: Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; ASCO: Career Development Award, Research Funding. Off Label Use: Drug: Oxaliplatin. Oxaliplatin combined with fludarabine, cytarabine, and rituximab has antileukemic activity in patients with relapsed/refractory Chronic Lymphocytic Leukemia and Richter Syndrome. Wierda:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Micromet: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Abbott Laboratories: Research Funding. O'Brien:Biogen Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding. Kipps:Sanofi Aventis: Research Funding. Jones:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbott Laboratories: Research Funding.

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Bendamustine in Monotherapy and in Combination Regimens in the Treatment of Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma – a Retrospective Analysis

Blood ◽

10.1182/blood.v120.21.4602.4602 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4602-4602

Author(s):

Iwona Hus ◽

Dariusz Jawniak ◽

Magdalena Gorska-Kosicka ◽

Aleksandra Butrym ◽

Justyna Dzietczenia ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Lymphocytic Leukaemia ◽

Cell Lymphoma ◽

Aggressive Lymphoma ◽

Rank Test ◽

Indolent Lymphoma ◽

Advisory Committees ◽

Log Rank Test ◽

Combination Regimens

Abstract Abstract 4602 Purpose: In this study, we carried out a retrospective analysis of the efficacy and toxicity of bendamustine in patients with B-cell lymphoproliferative diseases. Methods: Bendamustine was administered both in monotherapy and combined protocols in 111 patients, including 81 patients with chronic lymphocytic leukaemia (CLL), 20 patients with indolent lymphoma, and 10 patients with aggressive lymphoma (8 mantle cell lymphoma and 2 diffuse large B-cell lymphoma). Median age of patients was 61 years (range: 44 – 87 years). Almost all patients, except 3 previously untreated patients with CLL had relapsed (78 patients) or refractory disease (30 patients). 60.4% of patients were treated with bendamustine plus rituximab, while 28.2% received bendamustine in monotherapy, and 31.4% received other combined regimens. Results: Overall response rate (ORR) was 65.8%, including 20.7% of complete response (CR) and 45.1% of partial response (PR). In CLL patients, ORR was 59.3% with 16% of CR and 43.2% of PR. In patients with indolent NHL, ORR was 80%, including 30% of CR and 50% of PR. In patients with aggressive lymphoma, OR and CR rates were respectively: 90% and 40%. In patients with CLL, a likelihood of response was significantly lower in patients with ZAP-70 expression (p=0.006) and 17p deletion (p=0.009). Median overall survival (OS) for all patients was 11.5 months (range 1–40). For CLL patients, median OS was 11 months (range 1–40), for patients with indolent lymphoma 15.5 months (range 5–29 ) and for patients with aggressive lymphoma - 10 months (6–38). Median OS was significantly longer in patients responding to therapy as compared to non-responders (15 months vs. 8 months; p=0.0001). Median progression-free survival (PFS) in all patients was 6 months (0–38), including 4 months (0–38) for CLL patients, and 8.5 months (0–33) for patients with both aggressive and indolent lymphoma. Among pre-treatment parameters, β2-microglobulin (RR=1.234; p=0.002), haemoglobin level (RR=0.803; p=0.03) and PLT count (RR=1.005; p=0.03) significantly influenced survival. Also, the higher number of bendamustine cycles was associated with longer overall survival (RR=0.715; p=0.003). In patients with CLL, 17p deletion was associated with reduced overall survival (p=0.021; log-rank test). OS was significantly longer in patients who received ≤ 2 lines of previous therapies as compared to > 3 lines (p=0.018; log-rank test), and who received ≥ 4 courses of therapy (p=0.02; log-rank test). In patients with NHL, both OS and PFS were significantly longer in patients with lactate dehydrogenase level <250 U/l (p= 0.01; p=0.02; respectively), and who received ≥ 4 cycles of treatment (P= 0.03). Toxicity was predominantly haematological, including grade III/IV neutropenia in 32%, thrombocytopenia in 15% and anaemia in 16% of patients. Conclusion: Bendamustine, both in monotherapy and combination regimens, is an effective therapy with a favourable toxicity profile even in heavily pretreated patients. Disclosures: Hus: Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Glaxosmithkline: Consultancy. Off Label Use: In Europe bendamustine is indicated for first-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate and indolent non-Hodgkin's lymphomas as monotherapy in patients who have progressed during or within 6 months following treatment with rituximab or a rituximab containing regimen. Wiktor-Jedrzejczak:Genzyme: Speakers Bureau; Celgene: Speakers Bureau; Genopharm: Speakers Bureau; Bayer: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy; Janssen-Cilag: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Walewski:Roche: Honoraria, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Cephalon: Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Dmoszynska:Millenium Pharmaceuticals: Consultancy; Celgene: Consultancy; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Long-Term Outcome Of Patients With AL Amyloidosis Treated With High-Dose Melphalan and Stem Cell Transplantation: 19 Year Experience At a Single Center

Blood ◽

10.1182/blood.v122.21.3328.3328 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3328-3328 ◽

Cited By ~ 1

Author(s):

Vaishali Sanchorawala ◽

Gheorghe Doros ◽

Karen Quillen ◽

John Mark Sloan ◽

Anthony C Shelton ◽

...

Keyword(s):

Stem Cell ◽

Group Performance ◽

Performance Status ◽

Stem Cell Mobilization ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Term Survival ◽

Cell Mobilization

Abstract Aggressive treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic and clinical remissions associated with prolonged survival. We have performed 593 transplants from July 1994 to December 2012 in the Amyloidosis Center at Boston Medical Center/Boston University School of Medicine. Patients were enrolled in several sequential institutional review board–approved protocols during the 19-year study period. Eligibility criteria for all protocols required biopsy proof of amyloid disease; evidence of a plasma cell dyscrasia and exclusion of other types as appropriate; at least one major affected organ; and adequate measures of cardiac and pulmonary function, and performance status. Functional measures included cardiac ejection fraction 40% or greater, absence of symptomatic pleural effusions, absence of heart failure or arrhythmias resistant to medical management, oxygen saturation of 95% or greater on room air, lung diffusion capacity of 50% or more of predicted, supine systolic blood pressure of 90 mm Hg or greater, and Southwest Oncology Group performance status score of 2 or less unless limited by peripheral neuropathy. Age, renal function, time from diagnosis, prior therapy, and details of the conditioning regimen varied among the trials. Overall, the median age of patients treated with HDM/SCT was 57 years (range, 28-80). Treatment-related mortality (TRM) defined as death occurring within 100 days after SCT occurred in 51 patients, leading to overall TRM of 9% (n=51/593). Additionally, there were 11 deaths during stem cell mobilization and collection phase. No death has occurred since 2005 during stem cell mobilization and collection and TRM has improved to 5% (n=11/235). Total of 324 patients (55%) received full dose melphalan at 200 mg/m2 and 269 (45%) received modified dose melphalan at 100-140 mg/m2 per protocol, based upon age and organ function. Hematologic CR, as defined by international consensus criteria, occurred in 40% (n=202/508) of evaluable patients measured at 6-12 months post SCT; by intention-to-treat the CR rate was 34%. Hematologic CR occurred in 44% (n=129/291) patients who received 200 mg/m2 of HDM compared to 34% (n=73/217) patients who received 100-140 mg/m2 of HDM (chi square p=0.015). Hematologic relapse occurred in 40 patients (20%) with CR at a median of 3.9 years (range, 1.6-12.4). The median overall survival (OS) is 6.7 years with a median follow-up of 4.5 years. The median OS has not been reached for patients achieving a hematologic CR but exceeds 12.4 years, compared to 5.9 years for those not achieving CR (log-rank p<0.001). The median OS for patients following hematologic relapse is 3.5 years. Twenty-five % of patients are alive, up to 19 years after undergoing HDM/SCT. These data highlight the remarkable long-term survival results that can be obtained in patients with AL amyloidosis treated with HDM/SCT. While survival is strongly dependent upon achieving a hematologic CR, the survival of patients who do not achieve a CR and of those who relapse after CR also is notable, suggesting a benefit of treatment. Strategies to improve risk-stratification of patients and reduce TRM, as well as using sequential or combination therapies to increase the CR rate, will likely improve outcomes in the future for patients who just a few years ago were considered to have a rapidly fatal diagnosis. Disclosures: No relevant conflicts of interest to declare.

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