Achievement Of Hematologic Response Research Articles

Влияние поражения сердца на прогноз у пациентов с системным AL-амилоидозом

AIM. To assess the clinical features as well as the factors affecting prognosis and long-term treatment outcomes in systemic AL amyloidosis patients with cardiac involvement. MATERIALS & METHODS. The trial enrolled 123 systemic AL amyloidosis patients with cardiac involvement who were treated at the RM Gorbacheva Scientific Research Institute in 2004–2023. The patients were 34–85 years of age (median 61 years); there were 61 women (49.6 %) and 62 men (50.4 %). RESULTS. Cardiac disease grades 1, 2, 3a, and 3b were identified in 13.8 %, 50.4 %, 17.9 %, and 17.9 % of AL amyloidosis patients, respectively. Chronic cardiac failure (CCF) developed in 65.9 % (n = 81), and severe cardiac failure was detected in 25.4 % (n = 31) of patients. Most of them (90,2 %), despite CCF, preserved left ventricular ejection fraction (> 40 %) with the mean value of 59.6 % (range 33–78 %). The left ventricular stroke volume index (SVI) was below the normal values (< 41 mL/m2) in 92.7 % of patients. The mean SVI value was 26.1 mL/m2 (range 8.3–49.5 mL/m2). The lower SVI was associated with cardiac disease grades. This parameter appeared to be 30.9 mL/m2, 26.8 mL/m2, 24.8 mL/m2, and 21.4 mL/m2 in grades 1, 2, 3a, and 3b (p = 0.006), respectively. Total global strain (TGS) in the left ventricle myocardium was decreased (< 20 %) in 94.6 % of patients. The mean TGS value was 13.8 % (range 4.4–34.8 %). TGS was diminishing with increasing cardiac disease grade (grade 1 with 17.8 %, grade 2 with 14.6 %, grade 3a with 13.1 %, and grade 3b with 9.6 %) (p = 0.007). Atrial fibrillation was reported in 23 % of patients, supraventricular tachycardia was observed in 31.9 %, and supraventricular extrasystoles were registered in 39.7 %. Ventricular extrasystoles were found in 73.7 % of patients, and ventricular tachycardia was seen in 13.2 %. Sinoatrial block was reported in 6.6 % of patients, and atrioventricular block was identified in 19.8 %. Syncope occurred in 12.3 % of patients. An artificial cardiac pacemaker was implanted in 8 patients. The thromboembolism rate was 13 %: the myocardial infarction rate was 11.4 %, and the rate of acute cerebrovascular accidents was 5.7 %. Atrial clots were detected in 2 (1.6 %) patients. The cumulative incidence of hematologic response for 2 years was 57 % and did not depend on cardiac disease grade, the 2-year rate of cardiac response was 39.1 %. Before achieving hematologic and cardiac responses, mortality was 26.5 % and 29.9 %, respectively. The overall 5-year survival was 62.6 %, and the 5-year hematologic progression-free and major organ impairment-free survival was 39.3 %. Cox regression model confirmed 3 independent predictors of poor prognosis: the level of NT-proBNP ≥ 2500 pg/mL (p = 0.004), SVI < 25 mL/m2 (p = 0.0174), and prior syncope (p = 0.0191). The achievement of hematologic response had a positive effect on survival rates (p < 0.0001). CONCLUSION. A comprehensive assessment of cardiac damage by the time of primary AL amyloidosis diagnosis as well as appropriate treatment of this disease can reduce the risk of early cardiac mortality and enhance chances of not only achieving hematologic response but also improving survival rates.

Molecular markers as possible efficacy predictors of targeted therapy for myelofibrosis: single-center study

Background. Targeted therapy is the most promising in the treatment of myelofibrosis, but it is necessary to search for the reasons limiting its effectiveness. There are known factors negatively affecting the development of myelofibrosis, but data on their negative impact in the context of targeted therapy are scarce.Aim. Assessing the impact of cytogenetic and genetic abnormalities on the course and therapy results for primary and secondary myelofibrosis during ruxolitinib therapy.Materials and methods. The prospective study included 106 patients with myelofibrosis in the chronic phase (53 (50 %) men and 53 (50 %) women) who received ruxolitinib at the Moscow City Hematology Center, S.P. Botkin City Clinical Hospital. The median age of patients was 62 (18–84) years. The median disease duration before initiation of ruxolitinib therapy was 79 (1–432) months. Before therapy, genetic studies were performed, including next-generation sequencing. The median duration of ruxolitinib therapy was 33 (1–111) months. The influence of the cytogenetic landscape, driver mutations, allele burden of JAK2 (over time) and CALR, additional mutations on the dynamics of symptoms, spleen size, achievement of hematological response, overall survival, progression-free survival, survival without blast crisis and without progression of myelofibrosis with targeted therapy was assessed.Results. The studied genetic factors did not have a significant correlation with hemogram parameters. The hematological response in patients with JAK2 and CALR mutations compared favorably with the response in the groups with the MPL mutation and triple negative status (TNS). Higher hematological response rate was obtained in the group with initially low allele burden <50 % of JAK2 or CALR. Significant differences in 5-year overall survival were found between groups of patients with TNS and JAK2 and CALR mutations (p <0.05); with CALR allele burden <50 % and ³50 % before initiation of ruxolitinib therapy (p = 0.01); the presence or absence of positive dynamics of the JAK2 allele burden during treatment (p <0.05); additional mutations assigned to different pathogenicity groups (p <0.05); with different number of pathogenic mutations (1 or ³2), the presence or absence of pathogenic mutations in the ASXL1 (p = 0.002) and SETBP1 (p = 0.00001) genes. The 5-year progression-free survival was significantly different in cohorts of patients with or without positive dynamics of the JAK2 allelic load during treatment (p <0.05); additional mutations assigned to different pathogenicity groups (p <0.05); with a different number of pathogenic mutations (1 or ³2), the presence or absence of a pathogenic mutation of the SETBP1 gene (p = 0.003). Progression-free survival did not correlate with the type of driver mutation or its absence; however, all patients with TNS died from myelofibrosis progression. Significant differences in 5-year blast crisis-free survival were observed between groups with JAK2 and MPL mutations (p = 0.001), JAK2 and TNS (p = 0.002); difference in 5-year survival without progression of fibrosis – between groups with pathogenic and benign (p = 0.031); uncertain and benign (p = 0.001) mutations.Conclusion. The study identified genetic markers associated with decreased efficacy of ruxolitinib therapy.

Lack of Renal Recovery Predicts Poor Survival in Patients of Multiple Myeloma With Renal Impairment

BackgroundRenal impairment (RI) confers a poor prognosis in multiple myeloma. Reversibility of renal function is associated with improved survival in such patients. Patients in developing countries often present at an advanced stage and renal impairment is present in up to 40% of patients at diagnosis. We studied the renal outcome and survival of these patients with bortezomib-based induction therapy. Materials and MethodsIt was a single-center prospective study in a tertiary care multi-specialty institute in patients of newly diagnosed multiple myeloma (NDMM) who presented with RI from July 2018 to December 2019. The diagnosis of multiple myeloma was made based on IMWG14 criteria. All patients received bortezomib and or immunomodulatory drug-based triplet or quadruplet induction therapy. Hematological and renal outcomes were assessed as per IMWG 2016 criteria. ResultsAmong 216 consecutive patients of NDMM, RI was seen in 91 (42.2%) patients. The median age of 91 patients was 60 years. (range- 32-80 years). Light chain myeloma was seen in 26% (n = 24) of patients. The median estimated glomerular filtration rate (eGFR) was 15.36 mL/min (3.1-38 mL/min) and a majority of patients were in the advanced ISS stage. (ISS III = 85.7%). Thirty-six (39.5%) patients received hemodialysis at presentation. Renal response was seen in 67 (73%) patients and 20 (out of 36; 55%) became dialysis independent over a median time of 38 days (Range 15-160 days). At a median follow-up of 14.7 months, 30 (33%) patients had died, of which, 14 (15.4%) patients had early mortality (within 2 months of diagnosis). Presence of light chain myeloma and cast nephropathy (definite or probable) were identified as independent predictors of poor renal recovery on multivariate analysis. (HR = 2.841; 95% CI [1.471-5.486], P = .002 for light chain myeloma; HR = 1.859; 95% CI (1.087-3.180); P = .024 for cast nephropathy) Patients with low eGFR at presentation (<12.5 mL/min) were more likely to have persistent renal insufficiency. (HR-3.521; 95% CI (1.856-6.679), P = .000). Patients who attained sustained renal recovery had improved survival as compared to patients in whom renal function failed to improve. (median OS- not reached vs. 8.3 months, P = .000) Achievement of hematological response and independence from hemodialysis was associated with improved survival on multivariate analysis. ConclusionRenal impairment was reversible in almost three-fourths of NDMM patients. achievement of hematological response and hemodialysis independence were independent predictors of improved overall survival in NDMM patients with RI.

Predictive Factors of Overall Survival in Patients with Relapsed AL Amyloidosis Treated with Single Agent Daratumumab

Predictive Factors of Overall Survival in Patients with Relapsed AL Amyloidosis Treated with Single Agent Daratumumab

Persisting Cardiac Dysfunction and Quality of Response Predict Survival in Patients with AL Amyloidosis Who Respond to Upfront Therapy

Introduction. The presence and severity of heart involvement at diagnosis is by far the most important prognostic factor in AL amyloidosis, and our ability to prognosticate survival and assess response to therapy based on cardiac biomarkers has revolutionized the management of this disease. However, very little is known on the impact of persisting cardiac dysfunction after upfront chemotherapy in patients with AL amyloidosis. This is particularly relevant to identify subjects who can benefit most from the different therapies targeting amyloid deposits that are currently being tested in clinical trials in patients who still have cardiac dysfunction after successful upfront therapy.Methods. The prospectively maintained database of the Pavia Amyloidosis Research and Treatment Center was searched for patients who obtained at least a partial hematologic response (PR) after upfront therapy. Survival was measured from the time of best hematologic response to death or last follow-up. Cutoffs of N terminal pro natriuretic peptide type B (NT-proBNP) best predicting survival after response were identified by Receiver Operator Characteristic (ROC) analyses based on death at 2 years.Results. A total of 507 patients diagnosed between 2004 and 2015 were included in the study. Best hematologic response was achieved after a median of 3.6 months from upfront therapy initiation and was complete response (CR) in 22%, very good PR (VGPR) in 56%, and PR in 22%. At diagnosis the heart was involved in 77% of patients. After a median follow-up of living patients of 52 months, median overall survival (OS) from the time of best response was 76 months. Median OS by response category was not reached for CR, 78 months for VGPR (P=0.004 compared to CR), and 40 months for PR (P<0.001 compared to VGPR). The presence of heart involvement remained a predictor of poorer survival also after achievement of hematologic response (median 70 months vs. not reached, P<0.001). Baseline NT-proBNP was >650 ng/L (evaluable for cardiac response) in 347 patients (68%). Of them, 121 [35%, 95% confidence interval (CI) 29-42%] achieved a cardiac response by the time of best hematologic response. Cardiac response was associated with improved survival (median 86 vs. 46 months, P<0.001). The cutoff of NT-proBNP concentration best predicting survival after hematologic response was 3500 ng/L (median 16 vs. 93 months, P<0.001). Importantly, patients whose NT-proBNP was <3500 ng/L had a longer survival within each hematologic response category (CR median not reached vs. 74 months, P=0.012; VGPR median not reached vs. 21 months, P<0.001; PR median 50 vs. 4 months, P<0.001). At multivariate analysis achievement of CR/VGPR after upfront therapy [hazard ratio (HR) 0.54, 95%CI 0.39-0.75, P<0.001], a concentration of NT-proBNP above 3500 ng/L (HR 2.61, 95%CI 1.88-3.63, P<0.001), and NT-proBNP response (HR 0.68, 95%CI 0.48-0.98, P=0.036) were independent predictors of survival. The quality of response (achievement of CR/VGPR and/or cardiac response) and NT-proBNP concentration (cutoff 3500 ng/L) identified 3 groups with significantly different survivals after upfront therapy (Figure 1).Discussion. In AL amyloidosis heart dysfunction persisting after achievement of best hematologic response retains its ominous prognostic impact also in patients obtaining good quality hematologic response. A novel staging system incorporating NT-proBNP concentration and hematologic and cardiac response allows best prediction of survival of patients with heart involvement after response to upfront therapy, identifying those in greater need of further improving heart involvement and/or quality of hematologic response. [Display omitted] DisclosuresPalladini:Prothena: Honoraria, Other: Travel grant; Celgene: Other: Travel grants; Jannsen-Cilag: Membership on an entity's Board of Directors or advisory committees.

Clinicopathologic Predictors of Reversibility Dialysis Dependent Acute Kidney Injury in Patients with Myeloma Cast Nephropathy

Abstract Introduction: Myeloma cast nephropathy (MCN) is a main cause of acute kidney injury (AKI) at multiple myeloma (MM) onset. Wherein 5-9% of newly diagnosed MM patients are dialysis dependent. The introduction of novel agents has provided the achievement of rapid and deep hematologic response in most patients. However, the renal response in patients on dialysis is only 38-62.5%. The predictors of AKI reversibility in patients with MCN remain not enough studied. Aim: to determine clinical, morphological and immunohistochemical predictors of reversibility dialysis dependent AKI in patients with MCN. Materials and methods: 36 patients aged 38 to 74 years (median age=57 years) with newly diagnosed MM and dialysis dependent AKI stage 3 (AKIN, 2012) due to MCN were enrolled into the study from January 2006 till November 2019. The diagnosis of MM, hematologic and renal response were established according to the 2016 IMWG criteria. MCN was determined by renal biopsy performed prior to induction therapy. The assessment degree of acute tubular injury, tubular atrophy and interstitial fibrosis (IF/TA) were semi-quantitatively evaluated. The number of sclerotic glomerular were calculated manually. The median number of casts was defined by all casts in a section divided by number of fields observed (х100). Additionally, square of interstitial fibrosis, interstitial inflammation, expression of Immunohistochemical markers (E-cadherin, α-smooth muscle actin (α-SMA), vimentin) were measured by computerized quantitatively image analysis using the digital module Leica (Germany). The time from diagnosis of AKI to start of induction therapy did not exceed 3 months. Bortezomib based first line treatment regimen was used in 25 (69%) of patients; 9 (25%) patients received chemotherapeutic agents only, 2 (6%) dead before a start of induction therapy. Statistical software package SAS 9.4 was applied for calculations. Overall survival according to renal response was compared by using Kaplan-Meier curves. Also frequency, logistic, discriminant and ROC analysis were used. All estimates are shown with a 95%CI. Results: Hematologic partial response or better occurred in 19 (53%) of patients, median of 32 (13-129) days. Renal response - in 14 (39%). In 3 (8%) cases renal function improved after correction of dehydration before start of antimyeloma therapy, in the remaining 11 (30%) patients only when hematologic response was achieved (p = 0.001). The frequency of renal response was depending on start of antimyeloma therapy before and after 4 weeks from diagnosis of AKI and was 83% and 17%, respectively (p &amp;lt;0.05). In patients with renal response there was not a single fatal outcome; without renal response 3-year OS was 68% ± 13%. Patients with hematologic response were divided into two groups (Tab.). The main pathological findings associated with renal response were less frequent mild to severe IF/TA in patients with and without renal response (moderate 45% vs 75%, respectively, p=0.008), less area of interstitial fibrosis (24.9% vs 44.7%, respectively, p=0.001), percentage of proximal tubules with save epithelial phenotype and less area of expression E-cadherin at interstitium (15.9% vs 7.1%, respectively, p=0.006). The median number of casts per field was the same (6.4 and 6.3, p=0.64) as well as the percentage of tubule lumen obstruction by casts (13.6% and 15.1%, p=0.81). Statistically significant correlation between the expression area of E-cadherin and interstitial fibrosis was not found (Rs= -0.335, p= 0.065). Therefore, a combination of these factors can be used to predict renal response in the onset of AKI due to MCN (area under the ROC curve is 0.84). The prognostic model and logical rule allow to define groups of renal outcomes (Fig.). If expression area of E-cadherin is less than 10% and / or area of interstitial fibrosis is more than 40% of the interstitium, a renal response is unlikely (OR = 24.5) and will not be achieved in almost 90% of cases, despite hematological response. Discussion. Reversibility of dialysis dependent AKI due to MCN rely on the achievement of hematological response and the time from diagnosis of AKI to start of antimyeloma therapy. There are predictors of renal response of these patients determined by the severity of morphological changes: degree of IFTA, quantitative area of interstitial fibrosis and E-cadherin expression. Disclosures No relevant conflicts of interest to declare.

Factors Associated with Achieving Hematological Response in CML (Chronic Myeloid Leukemia) Patient

Background: The goal of CML therapy is to achieve complete hematological response first, then cytogeneticresponse andcomplete molecular response at the very end. Achieving a complete hematological responseis the easiest and relatively inexpensive to detect. Several factors are thought to have an association withachieving hematological response. This study sought to determine the factors associated with achievinghematological response in CML patientsMethod: We conducted an observational retrospective cohort study of CML patients at Wahidin SudirohusodoHospital and its network on 2018-2019 period. Diagnosis was done by positive BMP (Bone Marrow Punctie)results for CML, then a monthly blood check until a hematological response was achieved.Results: There wer 39 research subjects, 19 male (48.7%) and 20 female (51.3%). No association foundbetween age, gender and achievement of hematological response. Type of therapy was significantlycorrelated with the achievement of hematological response, with the highest number found in Nilotinibtherapy compared to other group. (54,1%; p = 0.046) Subjects who achieve hematological response had alower percentage of blast cells. (6.1% vs. 7.9% ; p = 0.016)Conclusion: The use of Nilotinib therapy was significantly associated with a succesful achievementof hematological response. A lower percentage of blast cells was found in CML patients who achievedhematological response.

Primary Results from the Phase 3 Tourmaline-AL1 Trial of Ixazomib-Dexamethasone Versus Physician's Choice of Therapy in Patients (Pts) with Relapsed/Refractory Primary Systemic AL Amyloidosis (RRAL)

Primary Results from the Phase 3 Tourmaline-AL1 Trial of Ixazomib-Dexamethasone Versus Physician's Choice of Therapy in Patients (Pts) with Relapsed/Refractory Primary Systemic AL Amyloidosis (RRAL)

Maladie de dépôts d’immunoglobulines monoclonales de type Randall : du diagnostic au traitement

Monoclonal immunoglobulin (Ig) deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain (LCDD), heavy chain (HCDD) or both (LHCDD) along basement membranes. MIDD should be suspected in patients presenting with glomerular proteinuria and monoclonal gammopathy, but none of these criteria is necessary for the diagnosis although renal involvement is prominent. Since an abnormal serum κ/λ ratio is found in virtually all MIDD patients, including those with HCDD, serum free light chain assay should be included in the initial workup in patients older than 50 presenting with kidney disease. Bortezomib-based regimens are efficient and well tolerated, resulting in improvement in both renal and global survival, comparatively to historical series. High dose melphalan with autologous stem cell transplantation may be proposed as second line therapy in selected patients. The achievement of hematological response, based on the difference between involved and uninvolved serum free light chains (dFLC), is mandatory. In a recent series, post-treatment dFLC<40mg/L was the major predictive factor of renal response and was associated with improvement of both renal and global survival. In MIDD, bortezomib-based therapy is safe and efficient when introduced early after diagnosis. dFLC response is a favorable prognostic factor for renal survival.

High-dose melphalan and peripheral blood stem cell transplantation for light-chain amyloidosis with cardiac involvement

AbstractHigh-dose melphalan (HDM) plus stem cell transplantation is an effective treatment for light-chain amyloidosis (AL), but is associated with high treatment-related mortality in patients with cardiac involvement. We studied 187 patients with cardiac involvement with AL who underwent HDM between 1996 and 2008. The median age was 57 years and the median time from diagnosis to HDM was 3.6 months. Half of the patients received reduced-dose melphalan (100-160 mg/m2). The median overall survival (OS) was 66 months, 54 months from diagnosis and HDM, respectively, and 91 patients (49%) were alive at the last follow-up 52 months (median) from HDM. Thirty patients (16%) died within 100 days of transplantation; only low serum albumin predicted early deaths. Overall, hematologic response (HR) and cardiac responses were seen in 66% and 41% of patients, respectively. The median OS for patients with and without HR was not reached and 22 months, respectively (P < .01); and for those with any decrease and no decrease in N-terminal-pro-brain natriuretic peptide was not reached and 26 months, respectively (P < .01). In multivariate analysis of baseline factors, only reduced-dose melphalan predicted shorter OS. HDM is feasible in patients with cardiac amyloidosis, and achievement of HR and organ response is associated with improved survival.

Clinical Characteristics and Outcome of Primary Systemic Light-Chain Amyloidosis in Greece

Primary systemic light-chain (AL) amyloidosis is characterized by the deposition of immunoglobulin light chain-derived amyloid fibrils in various tissues leading to multiorgan dysfunction. In order to define characteristics, treatment, and outcome of Greek patients with AL amyloidosis, we analyzed 112 unselected patients with AL from several hospitals. The heart was involved in 59% of patients and kidneys in 71%. Patients were treated with several different treatment regimens; high-dose dexamethasone-based regimens were used as primary treatment in 43% and melphalan-based regimens in 37%, while 12% received up-front bortezomib with dexamethasone. A hematologic response to first-line therapy was documented in 50% (complete response, 14.5%), and organ responses were observed in 25% of patients, the latter being strongly associated with achievement of hematologic response. Median overall survival was 34.2 months and was independently affected by heart involvement, creatinine, age, involvement of > or = 2 organs, and bone marrow plasmacytosis > 30%. In patients with cardiac involvement, advanced age and extended bone marrow plasmacytosis were associated with an even worse outcome, while for patients without heart involvement, only bone marrow plasmacytosis was independently associated with survival. Hematologic response was associated with improved survival in patients with heart involvement but mostly in patients with less bone marrow infiltration. In this first series of patients from Greece with AL amyloidosis, disease features and outcome appeared similar to those reported from tertiary centers. Heart involvement and bone marrow plasma cell infiltration comprise adverse prognostic factors but also indicate the heterogeneity of the disease and the need for individual treatment approaches.

Bortezomib With or Without Dexamethasone in Primary Systemic (Light Chain) Amyloidosis

PURPOSE To assess the efficacy and tolerability of bortezomib with or without dexamethasone and to define prognostic factors for patients with primary systemic light chain (AL) amyloidosis treated with bortezomib or both. PATIENTS AND METHODS Ninety-four patients from three centers were analyzed: 19% received the combination as first-line treatment, 81% had a median of two previous therapies, and 69% had refractory disease, while most patients had symptomatic heart involvement or elevated serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Results A hematologic response was achieved in 71% within a median of 52 days, including 25% complete responses (CRs). Previously untreated patients had a 47% CR rate. Age 65 years or younger (P = .043) and twice weekly administration of bortezomib (P = .041) were associated with higher response rates. A cardiac response was documented in 29% of patients, in most as sustained improvement of functional class and less often as a decrease in wall thickness. Hematologic responses were associated with a cardiac response and NT-proBNP reduction. After a median follow-up of 12 months, 29% of patients had organ progression and 27% had hematologic progression. Median survival has not been reached and the 1-year survival rate is 76%. Baseline NT-proBNP was independently associated with survival (P = .001), while in a landmark analysis, survival was associated with NT-proBNP reduction of > or = 30% (P = .006) and achievement of hematologic response (P = .001). Toxicity was manageable and mostly consisted of neuropathy, orthostasis, peripheral edema, and constipation or diarrhea. CONCLUSION Bortezomib with or without dexamethasone is active in AL amyloidosis and induces rapid responses and high rates of hematologic and organ responses. Serial measurement of cardiac biomarkers is a powerful predictor of outcome.

Comparison of various criteria in predicting treatment response and prognosis of patients with myelodysplastic syndrome treated with azacitidine

This study was performed to identify whether cytogenetics, International Prognostic Scoring System (IPSS), or World Health Organization Classification-Based Prognostic Scoring System are predictive of the efficacy of azacitidine in patients with myelodysplastic syndrome (MDS). We retrospectively reviewed the clinical records of 113 patients with MDS treated with azacitidine. The "response alternating disease natural history," "cytogenetic response," and "hematologic improvement" were assessed by serial bone marrow biopsy, cytogenetic study, and hemogram analyses. The complete and partial remission rates were 17.6% and 3.9% in 51 evaluable patients. There were no significant differences in response rate in the different cytogenetic/IPSS/WPSS groups. The overall hematologic response (HR) rate was 49.6%, and the HR rate was significantly greater in patients classed as "very high" risk according to the WPSS compared with other patient groups. The 1-year overall survival (OS) rate was higher among patients with HR compared with those without HR (80.9% vs 63.3%, p = 0.046), and the 1-year OS rate among patients classed as being at high risk by each criteria was similar to that of patients classed as being at low risk. The hazard ratio of death among patients with HR compared with those without HR was 0.17 (95% CI 0.04-0.69) for high + very high risk group based on WPSS. Patients in the WPSS high-risk group had an increased HR rate compared with other patient groups, and the achievement of HR was associated with a significant increase in OS. Azacitidine showed similar efficacy in all patient groups, even in patients with poor cytogenetics and in high-risk groups.

Subcutaneous omacetaxine mepesuccinate in chronic myeloid leukemia (CML) patients resistant or intolerant to two or more tyrosine kinase inhibitors (TKIs): Data from an ongoing phase II trial

7027 Background: Omacetaxine (OM), a first-in-class cetaxine, shows clinical activity against Ph+ CML with a mechanism of action independent to tyrosine kinase inhibition. Patients (Pts) who have failed multiple TKIs may benefit from an alternative therapy for CML. Methods: Pts include adult CML following resistance or intolerance to at least 2 TKIs. T315I+ Pts are enrolled in a separate trial. Pts receive OM induction at 1.25 mg/m2 subcutaneous (SC) BID for 14 days every 28 days followed by maintenance at 1.25 mg/m2 SC BID for 7 days every 28 days (maintenance after at least one induction cycle and achievement of hematologic response). Results: 60 pts (30 chronic phase [CP], 14 accelerated phase [AP], and 16 blast phase [BP] have been enrolled with 51% having failed at least 3 prior TKIs. Median age: 58 yrs; 50% male. Median disease duration: 74 months. At baseline, 38.5% of pts had Bcr-Abl mutations including 9.6% with compound mutations. The most frequently observed mutations were F317L (11.5%) and V299L (5.8%). OM is well tolerated with transient myelosuppression as the primary toxicity. Grade 3/4 non-hematologic events are rare with pyrexia occurring in 4.3% of patients. Efficacy data are available for 30 Pts: Conclusions: Omacetaxine in multi-TKI resistant or intolerant CML is well tolerated and has achieved hematologic and cytogenetic responses in these heavily pre-treated Pts. [Table: see text] [Table: see text]

Subcutaneous omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukemia (CML) patients (Pts) with the T315I mutation: Data from an ongoing phase II/III trial

7008 Background: Omacetaxine (OM), a first-in-class cetaxine shows clinical activity against Ph+ CML with a mechanism independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have no activity against T315I. Methods: Adult Pts with T315I+ CML following TKI failure received OM induction at 1.25 mg/m2 subcutaneous (SC) twice daily (BID) for 14 days every 28 days followed by maintenance at 1.25 mg/m2 SC BID for 7 days every 28 days (maintenance after at least one induction cycle and achievement of hematologic response). Results: 66 pts (39 chronic [CP], 16 accelerated [AP] and 11 blast phase [BP]) have been enrolled. All had failed prior imatinib and 80% failed ≥2 prior TKIs. Median age is 58 yrs. Median disease duration is 58 mos. OM is well tolerated with transient myelosuppression as the primary toxicity. Grade 3/4 non-hematologic events are diarrhea (2%) and fatigue (4%). Efficacy data are available for 44 Pts. In CP Pts, the median number of cycles is 4 (1–22) with 39% having received ≥ 6 cycles of therapy; 64% of Pts have had the T315I clone reduced to below detection limits; the 2-year progression free survival is 70%. Conclusions: Omacetaxine in T315I+ CML Pts results in de-selection of the T315I clone and induces hematologic and cytogenetic responses. [Table: see text] [Table: see text]

Melphalan and Dexamethasone Is an Effective Therapy for Primary Systemic Amyloidosis.

Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder with a poor survival, especially in patients (pts) with multiple organ involvement. For pts with limited organ involvement, high dose chemotherapy with autologous stem cell (SCT) support is an effective approach. However, the toxicity of SCT limits its widespread use. Melphalan and dexamethasone has been previously shown to be effective in pts ineligible for SCT.Methods: We reviewed our experience with melphalan and dexamethasone for treatment of AL. Eighty one pts were treated between 2001 and 2003; median age at start of therapy was 63 years (range, 38–80) and 56 pts (69%) were males. Among these, 46 pts (57%) had 2 or more major organs (cardiac, renal, hepatic) involved. Intravenous melphalan (IV) was used in 45 pts (56%), 32 (40%) received oral melphalan (PO) and the rest received cycles of both. The most common doses were 16 mg/m2 for IV administration (every 4–6 weeks) and 0.22 mg/kg for PO administration (every 4 weeks). Dexamethasone was usually given at a dose of 40 mg for the first 4 days of each cycle.Results: Patients received a median of 5 cycles (range; 1–17). At the time of analysis, 53 (65%) pts were alive with a median follow up of 10.8 months (range, 1.4–47.1).The estimated median overall survival (OS) was 25.6 months for the entire group, with the number or type of organs involved not impacting survival. Hematological response (HR) was defined by a 50% reduction in either serum M-spike, urine M-spike, or the absolute difference between the involved and uninvolved immunoglobulin free light chains. A HR was observed in 43 pts (67%) of the 64 pts measurable for HR by conventional criteria. Achievement of HR was associated with a superior OS with a median post-therapy OS that was not reached, while non-responders had a median OS of 11.1 months (p<0.0001) (Figure 1). Among these pts, an organ response as defined by conventional criteria, was seen in 14 pts (22%), which was significantly correlated with obtaining a hematological response (33% vs. 5%, p=0.01). A 25% reduction in the difference between the involved and uninvolved FLC strongly predicted prolonged OS, with a median post-therapy OS that was not reached for responders vs. 11.3 months for non-responders (p<0.0001) (Figure 2). A decrease in post-therapy brain natriuretic peptide (BNP) also predicted for a survival improvement, with the median OS not reached for responders vs. a median OS of 17 months for non-responders (p<0.016).Conclusion: Treatment with melphalan and dexamethasone is effective and a significant survival advantage is achieved in patients with a hematological response. FLC and BNP response can help identify patients that are likely to benefit from this therapy. [Display omitted] [Display omitted]

Renal Response After High-Dose Melphalan and Stem Cell Transplantation Is a Favorable Marker in Patients With Primary Systemic Amyloidosis

Primary systemic (AL) amyloidosis is a rare plasma cell disorder characterized by soft-tissue deposition of monoclonal light chain fragments. High-dose melphalan followed by autologous stem cell transplantation currently has become the treatment of choice. Favorable outcome is ensured with achievement of hematologic response, but little is known about organ response. This study was undertaken to determine the prognostic importance of renal response after high-dose melphalan and stem cell transplantation. All patients with AL amyloidosis who underwent autologous stem cell transplantation between 1996 and December 2002 were selected for study. Renal response is defined as a 50% or greater reduction in proteinuria with less than 25% decline in renal function. Exclusion criteria included pretransplantation dialysis therapy or dialysis dependence posttransplantation, treatment mortality, lack of proteinuria assessment posttransplantation, and baseline proteinuria with protein less than 1 g/d. Of 105 patients, 47 were excluded for stated reasons. Renal response was achieved in 60.3% of evaluated patients. Proteinuria was reduced by greater than 90% in 37.9% and returned to normal in 15.5%. Median response time was 12 months. Renal response was associated with a greater increase in serum albumin level (P = 0.001), maintenance of renal function (P < 0.001), and better survival (P = 0.0003). Renal responders had better survival regardless of hematologic response (P = 0.01 to 0.05). Currently, high-dose melphalan followed by stem cell transplantation is the most effective treatment for AL amyloidosis for those who are eligible. Our data show that renal response after high-dose melphalan followed by stem cell transplantation is associated with improved survival. Renal response is an independent marker of treatment success and can be used in cases in which determination of hematologic response is difficult.

Chronic myeloid leukemia in first chronic phase not responding to alpha-interferon: outcome and prognostic factors after autologous transplantation. EBMT Working Party on Chronic Leukemias.

We report the data obtained from the European Bone Marrow Transplant Registry for patients with CML who received autologous transplantation (AT) in chronic phase (CP) because alpha-IFN was ineffective. Forty-one CML patients (median age: 40.5 years; median Sokal index: 0.78) were included in this study. Bone marrow (16 cases) or blood (25 cases) progenitor cells were collected at diagnosis in 19 patients, during stable chronic phase or while the patient had cytogenetic (Cy) or complete hematologic response (CHR) in the other 22, and were manipulated ex vivo in 10 cases. The conditioning regimen consisted of busulfan associated with other chemotherapeutic regimens in 36 cases. Two patients died from interstitial pneumonitis (one case) and hemorrhage (one case). From the date of AT, the estimated probability of survival for the 41 patients was 84 +/- 13% and 51 +/- 29% at 2 and 4 years, respectively. Considering the 39 evaluable patients, the actuarial probability of achieving CHR, major and complete CyR 2 years after AT was 92 +/- 9%, 46 +/- 17%, and 30 +/- 15%, respectively. The Sokal score at diagnosis and the achievement of hematologic response after transplant were of prognostic importance. We suggest that a significant proportion of CML patients not responding to alpha-IFN may benefit from AT.

Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery.

The prognosis of invasive pulmonary aspergillosis (IPA) occurring in neutropenic patients remains poor. We studied whether new strategies for early diagnosis could improve outcome in these patients. Twenty-three histologically proven and 14 highly probable IPAs in 37 hematologic patients (neutropenic in 36) were analyzed retrospectively. The most frequent clinical signs associated with IPA were cough (92%), chest pain (76%), and hemoptysis (54%). Bronchoalveolar lavage (BAL) was positive in 22 of 32 cases. Aspergillus antigen test was positive in 83% of cases when tested on BAL fluid. Since October 1991, early thoracic computed tomographic (CT) scans were systematically performed in febrile neutropenic patients with pulmonary x-ray infiltrates. This approach allowed us to recognize suggestive CT halo signs in 92% of patients, compared with 13% before this date, and the mean time to IPA diagnosis was reduced dramatically from 7 to 1.9 days. Among 36 assessable patients, 10 failed to respond (amphotericin B [AmB] plus fluorocytosyne, n = 2; itraconazole + AmB, n = 8) and died of aspergillosis. Twenty-six patients were cured or improved by antifungal treatment (itraconazole with or without AmB, n = 22; voriconazole, n = 4). In 15 of 16 cases, surgical resection was combined successfully with medical treatment. Achievement of hematologic response, early diagnosis, unilateral pulmonary involvement, and highest level of fibrinogen value < 9 g/L were associated with better outcome. In febrile neutropenic patients, systematic CT scan allows earlier diagnosis of IPA. Early antifungal treatment, combined with surgical resection if necessary, improves IPA prognosis dramatically in these patients.