scholarly journals Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL

Blood ◽  
2012 ◽  
Vol 120 (26) ◽  
pp. 5185-5187 ◽  
Author(s):  
Max S. Topp ◽  
Nicola Gökbuget ◽  
Gerhard Zugmaier ◽  
Evelyn Degenhard ◽  
Marie-Elisabeth Goebeler ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Study Cohort ◽  
Clinical Relapse ◽  
Phase 2 ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Kaplan Meier ◽  
B Lineage

Abstract Persistence or recurrence of minimal residual disease (MRD) after chemotherapy results in clinical relapse in patients with acute lymphoblastic leukemia (ALL). In a phase 2 trial of B-lineage ALL patients with persistent or relapsed MRD, a T cell–engaging bispecific Ab construct induced an 80% MRD response rate. In the present study, we show that after a median follow-up of 33 months, the hematologic relapse-free survival of the entire evaluable study cohort of 20 patients was 61% (Kaplan-Meier estimate). The hema-tologic relapse-free survival rate of a subgroup of 9 patients who received allogeneic hematopoietic stem cell transplantation after blinatumomab treatment was 65% (Kaplan-Meier estimate). Of the subgroup of 6 Philadelphia chromosome–negative MRD responders with no further therapy after blinatumomab, 4 are in ongoing hematologic and molecular remission. We conclude that blinatumomab can induce long-lasting complete remission in B-lineage ALL patients with persistent or recurrent MRD. The original study and this follow-up study are registered at www.clinicaltrials.gov as NCT00198991 and NCT00198978, respectively.

scholarly journals Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome–Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study

2017 ◽  
Vol 35 (16) ◽  
pp. 1795-1802 ◽  
Author(s):  
Giovanni Martinelli ◽  
Nicolas Boissel ◽  
Patrice Chevallier ◽  
Oliver Ottmann ◽  
Nicola Gökbuget ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Disease Response ◽  
Minimal Residual

Purpose Few therapeutic options are available for patients with Philadelphia chromosome–positive (Ph+) B-precursor acute lymphoblastic leukemia (ALL) who progress after failure of tyrosine kinase inhibitor (TKI) −based therapy. Here, we evaluated the efficacy and tolerability of blinatumomab in patients with relapsed or refractory Ph+ ALL. Patients and Methods This open-label phase II study enrolled adults with Ph+ ALL who had relapsed after or were refractory to at least one second-generation or later TKI or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib. Blinatumomab was administered in 28-day cycles by continuous intravenous infusion. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles. Major secondary end points included minimal residual disease response, rate of allogeneic hematopoietic stem-cell transplantation, relapse-free survival, overall survival, and adverse events (AEs). Results Of 45 patients, 16 (36%; 95% CI, 22% to 51%) achieved CR/CRh during the first two cycles, including four of 10 patients with the T315I mutation; 88% of CR/CRh responders achieved a complete minimal residual disease response. Seven responders (44%) proceeded to allogeneic hematopoietic stem-cell transplantation, including 55% (six of 11) of transplantation-naïve responders. Median relapse-free survival and overall survival were 6.7 and 7.1 months, respectively. The most frequent AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Three patients had cytokine release syndrome (all grade 1 or 2), and three patients had grade 3 neurologic events, one of which (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events. Conclusion Single-agent blinatumomab showed antileukemia activity in high-risk patients with Ph+ ALL who had relapsed or were refractory to TKIs. AEs were consistent with previous experience in Ph– ALL.

Does ATRA Confirm to Play a Role in the Better Relapse Free Survival of Infants with Acute Lymphoblastic Leukemia?

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1515-1515
Author(s):  
Larisa Fechina ◽  
Egor Shorikov ◽  
Olga Streneva ◽  
Olga Khlebnikova ◽  
Igor Vyatkin ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Molecular Mechanisms ◽  
Treatment Approach ◽  
Lymphoblastic Leukemia ◽  
Relapse Free Survival ◽  
Standard Chemotherapy ◽  
Free Survival ◽  
Cox Regression Analysis

Abstract Abstract 1515 Treatment achievements in infant's acute lymphoblastic leukemia (ALL) are still very modest. Despite of many attempts, the creation of novel, based on the molecular mechanisms, clinically approved and safe therapy strategies for this group of patients (pts) seems to be slow, so far. We also have developed a new treatment approach for infants with acute leukemia – MLL-Baby protocol, which includes 1 or 2 weeks ATRA consecutive courses at the dosing schedule of 25 mg/m2/d adjusted to age, started immediately after induction completion, alternating with standard chemotherapy and/or simultaneously applied with re-inductions. Rationale for ATRA application and MLL-Baby details were introduced in our previous report (ASH 2007 Abstract #2828). We have described there a small group of 19 primary diagnosed ALL infants, who underwent MLL-Baby protocol treatment in comparison to the group treated by standard chemotherapy with 20 months (mo.) median of follow up. ATRA-containing regimen has been shown well tolerated and improved early relapse free survival (RFS) significantly. Aim. To re-assess the ATRA efficacy in more representative group of pts with longer time of follow up. From September 2003 108 pts with primary ALL younger 12 mo. were non-randomly allocated either to ATRA (+) treatment approach (MLL-Baby) – 75 pts or ATRA (-) standard chemotherapy (mainly ALL-MB) – 33 pts due to decision of the treating physicians from 24 participating clinics in Russia and Belarus. Parents' informed consent was signed in all cases. The trial was approved by Ethics Committees. Both ATRA (−) and ATRA (+) groups were similar by the initial characteristics: median age 6 (1–11) and 6 (0–11) mo.; m/f ratio 12/21 and 25/50; initial WBC 96,7 (0,7–940) and 83,9 (1,6–2058) per microliter respectively, although CNS involvement seems to be more frequent in ATRA (+) group: 4 (12%) and 18 (24%) pts correspondingly. MLL rearrangements (MLL pos.) were found in 15 (53,6%) from 28 examined ATRA (−) pts and in 53 (70,7%) from 75 ATRA (+) pts. BI phenotype predominance was evident in ATRA (+) group - 39 (52,7%) out of 74 examined pts. The number of pts who have achieved CR was equally high in both schedules: 28 (84,9%) and 67 (89,3%) but the relapses rates remains significantly different: 16 (57,1%) and 16 (23,8%) pts in ATRA (-) and ATRA (+) groups respectively (p=0,001). Eight years RFS is 0,36 ± 0,08 and 0,59 ± 0,06 (p=0,02); cumulative incidence of relapses (RCI) is 0,62 ± 0,01 and 0,31 ± 0,004 (p=0,03) in ATRA (−) and ATRA (+) groups correspondingly, although EFS: 0,54 ± 0,06 vs. 0,33 ± 0,08 (p=0,17) and OS: 0,59 ± 0,06 vs. 0,36 ± 0,08 (p=0,09), median of follow up - 36 mo. (2 - 105), did not differ significantly between 2 groups ATRA (+) and ATRA (−) respectively due to the high proportion of induction and remission deaths. Among 75 pts treated by MLL-Baby – 7 (9,3%) died in induction and 7 (10,4%) out of 67 pts who achieved CR died in remission with median time to death – 2 mo., mostly because of severe infections. Out of 46 MLL pos. pts from ATRA (+) group who achieved CR, 14 (30%) pts relapsed, RFS is 0,59 ± 0,08 and RCI 0,40 ± 0,007. In contrast, in ATRA (−) group the relapse incidence in MLL pos. pts was very high - 12 (80%) out of 15 pts who achieved CR (p=0,008), RFS is 0,20 ± 0,10 (p=0,01) and RCI 0,80 ± 0,01 (p=0,02) correspondingly. In univariate analysis the following risk-factors: age < 6 mo. (p=0,001); MLL rearrangements (p=0,004) and dexamethasone response on Day 8 (p=0,01) have a significant negative impact on EFS in group of pts treated by MLL-Baby. Cox-regression analysis confirms the negative value of the same risk-factors: MLL pos. status with Hazard Ratio (HR) 3,8 (95% CI 1,32-10,9) p=0,01; age HR 3,18 (95%CI 1,5–6,8) p=0,003 and Day 8 response HR 3,16 (95% CI 1,4–7,1) p=0,005. Conclusions. The updated results in our cohort of 75 patients demonstrated that ATRA confirms effectiveness in the relapses prevention in infants suffering from ALL, if used in combination with standard chemotherapy without any escalation and bone marrow transplantation. Although the molecular mechanisms of ATRA effect are still poorly understood and need to be deeply explored, it might be recommended for randomization within representative international studies, particularly to the MLL rearranged infant's ALL. Great efforts in non-relapse mortality reduction should be applied by all participating clinics. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Neural Network Analysis of Follow-Up Data in Primary Breast Cancer

2000 ◽  
Vol 15 (1) ◽  
pp. 116-122 ◽  
Author(s):  
N. Harbeck ◽  
R. Kates ◽  
K Ulm ◽  
H. Graeff ◽  
M. Schmitt
Keyword(s):  
Breast Cancer ◽  
Neural Network ◽  
Risk Group ◽  
Neural Network Analysis ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Kaplan Meier ◽  
The Neural Network ◽  
Pai 1

This paper reports on the performance of a recently developed neural network environment incorporating likelihood-based optimization and complexity reduction techniques in the analysis of breast cancer follow-up data with the goal of building up a clinical decision support system. The inputs to the neural network include classical factors such as grading, age, tumor size, estrogen and progesterone receptor measurements, as well as tumor biological markers such as PAI-1 and uPA. The network learns the structural relationship between these factors and the follow-up data. Examples of neural models for relapse-free survival are presented, which are based on data from 784 breast cancer patients who received their primary therapy at the Department of Obstetrics and Gynecology, Technische Universität München, Germany. The performance of the neural analysis as quantified by various indicators (likelihood, Kaplan-Meier curves, log-rank tests) was very high. For example, dividing the patients into two equally sized groups based on the neural score (i.e., cutoff = median score) leads to an estimated difference in relapse-free survival of 40% or better (80% vs. 40%) after 10 years in Kaplan-Meier analysis. Evidence for factor interactions as well as for time-varying impacts is presented. The neural network weights included in the models are significant at the 5% level. The use of neural network analysis and scoring in combination with strong tumor biological factors such as uPA and PAI-1 appears to result in a very effective risk group discrimination. Considerable additional comparison of data from different patient series will be required to establish the generalization capability more firmly. Nonetheless, the improvement of risk group discrimination represents an important step toward the use of neural networks for decision support in a clinical framework and in making the most of biological markers.

scholarly journals Increased Risk of Early Hematologic Toxicity during Maintenance Therapy in Acute Lymphoblastic Leukemia Patients of South Indian Origin Carrying NUDT15*3 Allele

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5059-5059
Author(s):  
Sunitha Kodidela ◽  
Dorababu Patchva ◽  
Dimpal Thakkar: ◽  
Biswajit Dubashi ◽  
Rajan Sundaram ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Candidate Genes ◽  
Genetic Variants ◽  
Lymphoblastic Leukemia ◽  
Relapse Free Survival ◽  
Free Survival ◽  
South Indian ◽  
Grade 3 ◽  
Methotrexate Polyglutamate

Background and Objectives: Globally the survival of ALL has increased tremendously with the five-year overall survival (OS) reaching 90% in high-income countries (HICs) (1, 2). However, in India, the five-year OS has been reported to be 30-70 %( 3) and deaths due to treatment related toxicity (TRT) in ALL were ranged from 2-24 % (4), which is ten times higher compared to HICs suggesting increased susceptibility to the toxicity of the chemotherapeutic drugs. This could be due to frequent variants in candidate genes determining the pharmacodynamic response or pharmacokinetics of the chemotherapeutic drugs used during maintenance therapy of ALL. Variations in the patient management, supportive care therapy are the other possible reasons of this increased incidence of TRT. Many patients are lost to follow-up due to the TRT, and eventually will die of the disease progression. The present study aimed to explore the association of common genetic variants in the candidate genes with early treatment related hematological toxicities (grade 3-4) in patients with Acute Lymphoblastic Leukemia (ALL) receiving low-dose MTX (LDMTX) and 6-Mercaptopurine (6-MP) based maintenance therapy. Materials and Methods: This prospective study was conducted between August 2011 and May 2016 and approved by institutional scientific and ethics committees. A total of 71 patients (43 males and 28 females aged between 1-51 years) with ALL were enrolled in the study after obtaining written informed consent and in the case of children, from legally accepted guardians. Patients below 25 years of age were treated using protocol-841 (MCP) I2A and those older than 25 years were treated with modified GMALL-84 protocols. MTX and 6-MP doses did not differ across both the protocols during maintenance therapy. Germline DNA samples collected at the time of remission from peripheral mononuclear cells was used to genotype15 selected variants frequent in the following candidate genes : ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15 using allele discrimination assay by real-time PCR. LC-MS/MS method was used to measure methotrexate polyglutamate (MTXPG3-5) levels in RBC's.Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE-version 4.03). Early grade 3-4 hematological toxicities occurring within first 100 days of the maintenance therapy was studied for its association with the genetic variants and other risk factors. Cumulative incidence curves were plotted and a risk factor analysis was performed using multivariate Cox regression. Co-linearity between variables was assessed. We used a back-ward selection method, retaining those variables with P-values<0.05 in the final model. Data analysis was done using statistical software « R ». Results: The cumulative incidences of early hematological TRT (grade 3-4) and relapse were 54.9 %, and 38.0 %, respectively. The relapse free survival was 59.2 %. The median follow-up of all patients from the start of maintenance was 1018 days. In multivariate analysis including all genetic variants, age, and WBC counts at diagnosis, we observed a significant increase in the risk of TRT in carriers of NUDT15*3 allele(rs116855232 ; p=0.002 ; univariate Hazards ratio : 2.81 (95% CI : 1.41-5.59). 3435C>T variant in ABCB1 gene showed a trend of association with that of relapse free survival. Neither the genetic variants studied were associated with the methotrexate polyglutamate levels, nor were the levels associated with the clinical outcomes. Conclusion: The NUDT15*3 allele carriers status could be used as one of the stratifying markers in South Indian ALL patients at the time of diagnosis to distinguish high and low-risk patients to develop early hematological toxicity, especially related to 6-mercaptopurine based ALL maintenance therapy protocols. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sequential CD19- and CD22-CART Cell Therapies for Relapsed B-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2126-2126 ◽  
Author(s):  
Shuangyou Liu ◽  
Biping Deng ◽  
Yuehui Lin ◽  
Zhichao Yin ◽  
Jing Pan ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Car T Cells ◽  
Car T

Abstract With traditional therapies, the prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is extremely poor. Chimeric antigen receptor (CAR) T cell therapy targeting at CD19 has demonstrated a significant efficacy on refractory/relapsed (r/r) B-ALL, but single-target CART could not maintain a long-term remission. Recently, CD22-CART has also shown an exciting result in r/r B-ALL. Here we sequentially applied CD19- and CD22-specific CART cells to treat relapsed B-ALL post-HSCT and observed the therapeutic effect. From June 30,2017 through May 31,2018, twenty-four B-ALL patients (pts) relapsing after allo-HSCT with both antigens CD19 and CD22 expression on blasts were enrolled, the median age was 24 (2.3-55) years. Seventeen pts had hematologic relapse, 6 with both bone marrow and extramedullary (EM) involvements and 1 with EM disease (EMD) only. Fourteen pts had failed to previous therapies including chemotherapy, donor lymphocyte infusion, interferon and even murinized CD19-CART in other hospitals. Recipient-derived donor T cells were collected for producing CAR-T cells, which were transfected by a lentiviral vector encoding the CAR composed of CD3ζ and 4-1BB. Eighteen pts were initially infused with murinized CD19-CART, then humanized CD22-CART; while 6 pts (5 failed to prior murinized CD19-CART and 1 had bright CD22-expression) were initially infused with humanized CD22-CART, then humanized CD19-CART. The time interval between two infusions was 1.5-6 months based on patients' clinical conditions. The average dose of infused CAR T cells was 1.4×105/kg (0.4-9.2×105/kg) for CD19 and 1.9×105/kg (0.55-6.6×105/kg) for CD22. All patients received fludarabine with or without cyclophosphamide prior to each infusion, some pts accepted additional chemo drugs to reduce the disease burden. Treatment effects were evaluated on day 30 and then monthly after each CART, minimal residual disease (MRD) was detected by flow cytometry (FCM) and quantitative PCR for fusion genes, EMD was examined by PET-CT, CT or MRI. Sixteen patients finished sequential CD19- and CD22-CART therapies. Three cases could not undergo the second round of CART infusion (1 died, 1 gave up and 1 developed extensive chronic graft-versus-host disease (GVHD)). The rest of 5 pts are waiting for the second CART. After first T-cell infusion, 20/24 (83.3%) pts achieved complete remission (CR) or CR with incomplete count recovery (CRi), MRD-negative was 100% in CR or CRi pts, 3 (12.5%) cases with multiple EMD obtained partial remission (PR), and 1 (4.2%) died of severe cytokine release syndrome (CRS) and severe acute hepatic GVHD. Sixteen patients (15 CR and 1 PR) underwent the second CART therapy. Before second infusion, 3/15 pts in CR became MRD+ and others remained MRD-. On day 30 post-infusion, 1 of 3 MRD+ pts turned to MRD-, 1 maintained MRD+ ( BCR/ABL+) and 1 had no response then hematologic relapse later. The PR patient still had not obtained CR and then disease progressed. As of 31 May 2018, at a median follow-up of 6.5 (4-10) months, among 16 pts who received sequential CD-19 and CD-22 CART therapies, 1 had disease progression, 2 presented with hematological relapse and 2 with BCR/ABL+ only, the overall survival (OS) rate was 100% (16/16), disease-free survival (DFS) was 81.3% (13/16) and MRD-free survival was 68.8% (11/16). CRS occurred in 91.7% (22/24) pts in the first round of T-cell infusion, most of them were mild-moderate (grade I-II), merely 2 pts experienced severe CRS (grade III-IV). The second CART only caused grade I or no CRS since the leukemia burden was very low. GVHD induced by CART therapy was a major adverse event in these post-HSCT patients. After the first CART, 7/24 (29.2%) pts experienced GVHD, of them, 4 presented with mild skin GVHD, 2 with severe hepatic GVHD (1 recovered and 1 died), and 1 developed extensive chronic GVHD. No severe GVHD occurred in the second infusion. Our preliminary clinical study showed that for B-ALL patients who relapsed after allo-HSCT, single CD19- or CD22- CART infusion resulted in a high CR rate of 83.3%, sequentially combined CD19- and CD22-CART therapies significantly improved treatment outcome with the rate of OS, DFS and MRD-free survival being 100%, 81.3% and 68.8%, respectively, at a median follow-up of 6.5 months. The effect of CART on multiple EMD was not good and CART induced GVHD needs to be cautious. Disclosures No relevant conflicts of interest to declare.

Age up to 75 Years Does Not Influence the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3501-3501
Author(s):  
Dipenkumar Modi ◽  
Abhinav Deol ◽  
Seongho Kim ◽  
Kendra Mellert ◽  
Marie Ventimiglia ◽  
...  
Keyword(s):  
Overall Survival ◽  
Relapse Rate ◽  
Cumulative Incidence ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity

Abstract Introduction: Patients with AML and MDS who are age 60 or above represent a discrete group of patients with a different disease biology compared to younger patients. These patients are often not offered allogeneic hematopoietic stem cell transplant (HSCT) as a curative intent because of concern of increased nonrelapse mortality (NRM) and poor overall survival (OS). Hence, the information on transplant outcomes among this population is very limited. Recently with the use of better supportive care measures and reduced intensity preparative regimens, patients greater than 60 are often recommended to proceed to transplant. This study evaluates our single center experience of allogeneic transplantation in patients with MDS and AML aged 60 and older. Patients and Methods: We retrospectively evaluated 60 years or older consecutive patients with AML and MDS who underwent allogeneic HSCT between January 2005 and December 2014. The primary objectives of our study were to determine NRM, relapse, relapse free survival (RFS) and OS at 1 year following transplant. The secondary objectives were to estimate cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD) at 1 year, length of stay and readmission rate in the first 100 days following transplant. Results: Between January 2005 and December 2014, 159 patients underwent allogeneic HSCT with the median age of 64 (range, 60-75) years and median follow-up duration for OS of 3.34 (95% CI, 2.51-3.87) years. Increasing number of patients were transplanted in recent years, i.e., 67% patients between 2010-2014 compared to 33% between 2005-2009. One hundred three patients (65%) had AML and 56 patients (35%) had MDS. Forty-nine patients (31%) received full intensity regimen and 110 patients (69%) received reduced intensity regimen. Fifty-two patients (33%) underwent allogeneic related transplant and 107 patients (67%) had allogeneic unrelated transplant. Thymoglobulin based GVHD prophylaxis was given in 77 patients (48%) whereas non-thymoglobulin based GVHD prophylaxis was given in 82 patients (52%). The median day to neutrophil and platelet engraftment was 11 (range, 7-22) days and 16 (range, 0-675) days, respectively. Graft failure occurred in 3 patients. At 1-year follow-up, the cumulative incidence of grade II-IV aGVHD was 39.7% (95% CI, 32.0-47.2%), grade III-IV aGVHD was 20.8% (95% CI, 14.9-27.5%) and cGVHD was 54.1% (95% CI, 46.0-61.5%). The cumulative incidence of chronic extensive GVHD was 39.8% (95% CI, 32.1-47.4%). Blood stream infection, cytomegalovirus reactivation, Epstein-Barr virus reactivation, C. difficile diarrhea occurred in 44%, 35%, 22% and 26% of patients, respectively. At 1-year follow-up, NRM was 25.3% (95% CI, 18.8-32.3%), RFS was 53.3% (95% CI, 46.1-61.7%), relapse rate was 21.4% (95% CI, 15.4-28.1%) and OS was 56.4% (95% CI, 49.2-54.7%). The median day of hospitalization following transplant was 26 (range, 19-112) days and almost half (52%) of patients were readmitted in the first 100 days following transplant. Leukemia recurrence was the most common cause of death. Multivariable analysis demonstrated high disease risk index to be the independent predictor of poor RFS, OS and higher relapse rate (p<0.03), whereas non-thymoglobulin based GVHD prophylaxis, higher comorbidity index (≥3) and MDS were found to be associated with higher NRM (p<0.03). Most importantly, age did not shown to have any effect on relapse rate, OS, RFS, or NRM. Conclusion: Our results indicate that allogeneic HSCT is well tolerated and had acceptable NRM, and OS among this group. Hence, older age alone should not be considered a contraindication to HSCT. Figure 1 Overall survival (OS) and relapse-free survival (RFS) estimates. The median OS is 1.60 years (95% CI, 0.94 to 5.00 years) and the median RFS is 1.15 years (95% CI, 0.63 to 3.07 years). The median follow-up time of OS and RFS are 3.34 years (95% CI, 2.51 to 3.87 years) and 3.25 years (95% CI, 2.51 to 3.87 years), respectively. Figure 1. Overall survival (OS) and relapse-free survival (RFS) estimates. The median OS is 1.60 years (95% CI, 0.94 to 5.00 years) and the median RFS is 1.15 years (95% CI, 0.63 to 3.07 years). The median follow-up time of OS and RFS are 3.34 years (95% CI, 2.51 to 3.87 years) and 3.25 years (95% CI, 2.51 to 3.87 years), respectively. Figure 2 Cumulative incidences of aGVHD, cGVHD, relapse and non-relapse mortality after transplantation. Figure 2. Cumulative incidences of aGVHD, cGVHD, relapse and non-relapse mortality after transplantation. Disclosures Deol: Jazz Pharmaceuticals: Consultancy.

scholarly journals Clinical features and survival outcomes of ocular melanoma in a multi-ethnic Asian cohort

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Laura Ling Ying Tan ◽  
Jiancheng Hong ◽  
Wei Lin Goh ◽  
Esther Wei Yin Chang ◽  
Valerie Shiwen Yang ◽  
...  
Keyword(s):  
Ocular Melanoma ◽  
Smoking History ◽  
Survival Outcomes ◽  
Study Cohort ◽  
Significant Independent Predictor ◽  
Free Survival ◽  
Southeast Asians ◽  
Kaplan Meier ◽  
Asian Cohort

Abstract Ocular melanomas are uncommon cancers in Southeast Asia unlike in the West. We conducted a retrospective review of patients (n = 44) with histologically-proven ocular melanoma within a multi-ethnic Asian cohort from Singapore. Clinicopathological features and relapse patterns were examined, and survival outcomes of interest included recurrence-free survival (RFS) and overall survival (OS). Survival analysis was performed using the Kaplan–Meier method and multivariable Cox proportional regression. The study cohort included 18 male and 26 female patients, with a median age of 52 years (range 8–78). Median follow-up was 154 months. For uveal melanomas (n = 29), the 5-year RFS and OS was 56.8% and 76.6%, respectively; whilst for conjunctival melanomas (n = 15), the 5-year RFS and OS was 30.1% and 68.8%, respectively. Fifteen patients (38.5%) eventually developed metastasis, following which the median survival was only 17 months. Multivariate analysis demonstrated that higher T stage was a significant independent predictor for both OS (HR 8.69, 95% CI 1.03 to 73.09, p = 0.047) and RFS (HR 11.62, 95% CI 2.45 to 55.00, p = 0.002). Smoking history was independently predictive of better RFS (HR 0.08, 95% CI 0.01 to 0.78, p = 0.030). In conclusion, our study demonstrates the poor ocular melanoma outcomes in Southeast Asians, highlighting the necessity for urgent research in this area of unmet clinical need.

scholarly journals Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 150
Author(s):  
Amber Gibson ◽  
Adriana Trabal ◽  
David McCall ◽  
Sajad Khazal ◽  
Laurie Toepfer ◽  
...  
Keyword(s):  
T Cell ◽  
Pediatric Population ◽  
Lymphoblastic Leukemia ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
The Mean ◽  
Lost To Follow Up

Venetoclax is approved for adult patients with chronic lymphocytic leukemia and acute myeloid leukemia. Expanding its use to the pediatric population is currently under investigation, but more robust data are needed. We retrospectively analyzed the safety and efficacy of venetoclax in children/AYA with ALL/LBL. We identified 18 patients (T-cell ALL, n = 7; T-cell LBL, n = 6; B-cell ALL, n = 5) aged 6–22 years. No new venetoclax safety signals were identified; the most common toxicity was myelosuppression. No deaths occurred within 30 days from the start of the therapy. A mean of 2.6 (range 0–8) prior lines of therapy were given. The mean duration of venetoclax was 4.06 months (range 0.2–24.67 months). Complete remission was achieved in 11 (61%) patients. Of the eight patients who remain alive, four are continuing on venetoclax combination therapy, and four proceeded to hematopoietic stem cell transplantation. Three patients who initially achieved CR, later relapsed, and are deceased. Nine patients are deceased, and one patient was lost to follow-up. Overall survival is 9.14 months (range 1.1–33.1), and progression-free survival is 7.34 months (range 0.2–33.1). This is the largest cohort of pediatric/AYA patients who received venetoclax for ALL/LBL. Our data support the consideration of venetoclax-based regimens in pediatric patients with R/R ALL/LBL and its investigation as upfront therapy for T-cell ALL/LBL.

scholarly journals Combination Chemotherapy Plus Dasatinib Leads to Comparable Rates of Overall Survival and Relapse-Free Survival As Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Positive Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4629-4629
Author(s):  
Jeremy Chang ◽  
Golnaz Vahdani ◽  
George Yaghmour ◽  
Kum-Ja Lee ◽  
Ashley Weissman ◽  
...  
Keyword(s):  
Combination Chemotherapy ◽  
Survival Benefit ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Transplant Patients ◽  
Significant Difference

Abstract Introduction: The presence of the Philadelphia chromosome has historically been associated with a poor prognosis in patients with acute lymphoblastic leukemia (ALL). Prior studies had demonstrated that the 5-year overall survival (OS) rate among adult patients with Philadelphia-chromosome positive (Ph+) ALL was 25% compared to 41% in Philadelphia-chromosome negative (Ph-) ALL (Moorman et. al. Blood 2007). While hematopoietic stem cell transplantation (HSCT) has long been regarded as the standard of care for adult Ph+ ALL patients despite its significant transplant-related morbidity and mortality, its benefit is less clear in the era of newer-generation tyrosine kinase inhibitors (TKI) such as dasatinib. Methods: We conducted a retrospective study at a single urban transplant center with academic affiliation to analyze the outcomes of adult patients diagnosed with Ph+ ALL between 2005-2018. Patients were treated with either combination chemotherapy plus dasatinib or combination chemotherapy plus dasatinib and allogeneic HSCT. Chemotherapy regimens included hyper-CVAD, Berlin-Frankfurt-Munster-like (BFM-like) protocol, and a regimen developed at the University of Southern California (USC ALL regimen) using pegaspargase (Douer et. al. Journal of Clinical Oncology 2014). All patients in both the transplant group and the non-transplant group received TKI therapy with dasatinib throughout their treatment courses; in the former, patients received dasatinib both prior to and following their transplants. Statistical analysis was performed using the Fisher Exact Probability Test with p-values <0.05 deemed significant. Results: A total of 71 Ph+ ALL patients were included in this study. Forty-three patients (60.5%) were male and the median age at the time of diagnosis was 44 years (range 20-69). Median follow-up time was 15 months (range 1-131). Chemotherapy regimens included the USC ALL regimen in 69.8% of patients, hyper-CVAD in 25.6%, and BFM-like protocol in 7%. While in remission, 31 (43.6%) patients underwent allogeneic HSCT with subsequent post-transplant dasatinib therapy. Median time of dasatinib initiation following transplant was at day 102. Matched related donor transplants were performed in 48% of patients, matched unrelated donor transplants in 24%, and haploidentical donor transplants in 29% of patients. In comparing OS rates, 1-year OS was 92.9% vs. 100% (p = 0.49), 2-year OS was 90.1% vs. 83.3% (p = 0.60), and 3-year OS was 75% vs. 62.5% (p = 0.64) in the allogeneic HSCT group compared to the non-transplant group, respectively (Figure 1). The 3-year relapse-free survival (RFS) rates also proved to be similar at 70.5% in the allogeneic HSCT group and 80.1% in the non-transplant group (p = 0.94, Figure 2). In addition, 37% of patients had a poor prognostic factor of a white blood count (WBC) >30 x 109/L at the time of diagnosis. When comparing rates of OS and RFS between transplant vs. non-transplant patients in this group, there was also no significant difference. Conclusion: This study showed that in the management of adult Ph+ ALL patients, there was no significant difference in OS or RFS between patients who underwent allogeneic HSCT compared to those who received only combination chemotherapy with dasatinib. In addition, prior studies of Ph+ ALL patients treated with either chemotherapy alone or chemotherapy followed by HSCT concluded that the OS rates were approximately 50%, 35%, and 30% at the 1-year, 2-year, and 3-year marks, respectively (Rowe et. al. Blood 2005). Our analysis, however, demonstrated improved rates of survival at all time points for this patient population with the addition of dasatinib. Subgroup analysis of patients with a WBC >30 x 109/L at the time of diagnosis also showed no significant difference in OS between transplant and non-transplant patients despite previous reports showing a survival benefit from HSCT (Huang et. al. Blood 2016). This may be attributed to the fact that our patients received the newer and more potent agent dasatinib compared to imatinib in these prior studies. Since allogeneic HSCT demonstrated no survival benefit in our study and can also introduce risks of serious infectious complications, venoocculsive disease (VOD), and graft-versus-host disease (GVHD) that contribute to patient morbidity and mortality, it may serve a less beneficial role for the Ph+ ALL population in the era of newer-generation TKIs. Disclosures No relevant conflicts of interest to declare.

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