This document summarizes research on treatments for thalassemia, including hematopoietic stem cell transplantation (HSCT) and gene therapy. It discusses outcomes of HSCT using different donor types and conditioning regimens in Thailand. It also presents initial results from a gene therapy clinical trial showing production of gene-modified hemoglobin and polyclonal engraftment without safety issues in the first few treated patients. The research demonstrates favorable outcomes of HSCT for thalassemia and potential for gene therapy to cure patients by adding modified genes to their own blood stem cells.
HCT and Gene Therapy for Thalassemia Major
Mark Walters, M.D.
January 18, 2014
Thalassemia Patient and Family Conference
Northern California Comprehensive Thalassemia Center
Children's Hospital Oakland
HCT and Gene Therapy for Thalassemia Major
Mark Walters, M.D.
January 18, 2014
Thalassemia Patient and Family Conference
Northern California Comprehensive Thalassemia Center
Children's Hospital Oakland
Allogeneic hematopoietic stem cell transplantation (allo HSCT) from an HLA-matched related donor provides the most potent anti-leukemic effect of any post-remission therapy in AML, as demonstrated by the lowest rates of relapse.
Graft vs leukemia plays and important role here.
Provides the best chance of long-term survival
Bone marrow transplantation for thalassemia in lower resource settings - The Cure2Children Foundation experience in Pakistan. By Dr Naila Yaqub, Assistant Professor, Bone Marrow Transplant unit, The Children hospital, PIMS, Pakistan
chimeric antigen receptor, its structure and role in killing tumor cells,mechanism of antitumor killing, car's in clinic,evolution of cars and new chimeric antigen models
Leveraging BCMA-Directed Therapies for Improved Patient Outcomes in Relapsed/...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Rahul Banerjee, Assistant Professor at the University of Washington and Fred Hutchinson Cancer Center, will provide a case-based discussion on leveraging BCMA-directed antibody-drug conjugates, CAR T-cell therapies, and bispecific T-cell engagers to improve outcomes for patients with multiple myeloma in need of additional treatment options.
STATEMENT OF NEED
Multiple myeloma is a disease that remains incurable for most patients, many of whom become refractory to the majority of available treatments (Kumar et al, 2022). It is estimated that 35,730 new cases of multiple myeloma are diagnosed in the United States annually, and 12,590 people die of the disease (Siegel et al, 2023). Agents targeting B-cell maturation antigen (BCMA), including antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers, represent a promising therapy class for patients in need of additional treatment options, including those with higher genetic risk and heterogeneity (Kumar et al, 2022). This activity led by Rahul Banerjee, MD, FACP, Assistant Professor in the Division of Medical Oncology at the University of Washington and Fred Hutchinson Cancer Center, will provide strategies for leveraging BCMA-directed therapies for improved patient outcomes in relapsed/refractory multiple myeloma.
TARGET AUDIENCE
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with multiple myeloma (MM).
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to:
Evaluate the mechanisms of action, efficacy, and safety of BCMA-directed therapies in relapsed/refractory MM
Assess guideline-recommended combination and sequential treatment strategies for relapsed/refractory MM
Identify risk factors for the development of treatment-specific adverse events with different classes of BCMA-directed therapies
Describe mechanisms of drug resistance/loss of response to BCMA-directed therapies
Examine the roles of gene expression profiling, soluble BCMA, and measurable residual disease (MRD) in clinical practice.
Optimizing Treatment Sequencing for Patients With Relapsed/ Refractory Multi...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Shaji Kumar, MD, Professor of Hematological Malignancies
Mayo Clinic Cancer Center, offers expert insight on the assessment of MM, emerging and current therapies, cutting edge approaches to personalized treatments plans, and much more.
Allogeneic hematopoietic stem cell transplantation (allo HSCT) from an HLA-matched related donor provides the most potent anti-leukemic effect of any post-remission therapy in AML, as demonstrated by the lowest rates of relapse.
Graft vs leukemia plays and important role here.
Provides the best chance of long-term survival
Bone marrow transplantation for thalassemia in lower resource settings - The Cure2Children Foundation experience in Pakistan. By Dr Naila Yaqub, Assistant Professor, Bone Marrow Transplant unit, The Children hospital, PIMS, Pakistan
chimeric antigen receptor, its structure and role in killing tumor cells,mechanism of antitumor killing, car's in clinic,evolution of cars and new chimeric antigen models
Leveraging BCMA-Directed Therapies for Improved Patient Outcomes in Relapsed/...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Rahul Banerjee, Assistant Professor at the University of Washington and Fred Hutchinson Cancer Center, will provide a case-based discussion on leveraging BCMA-directed antibody-drug conjugates, CAR T-cell therapies, and bispecific T-cell engagers to improve outcomes for patients with multiple myeloma in need of additional treatment options.
STATEMENT OF NEED
Multiple myeloma is a disease that remains incurable for most patients, many of whom become refractory to the majority of available treatments (Kumar et al, 2022). It is estimated that 35,730 new cases of multiple myeloma are diagnosed in the United States annually, and 12,590 people die of the disease (Siegel et al, 2023). Agents targeting B-cell maturation antigen (BCMA), including antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers, represent a promising therapy class for patients in need of additional treatment options, including those with higher genetic risk and heterogeneity (Kumar et al, 2022). This activity led by Rahul Banerjee, MD, FACP, Assistant Professor in the Division of Medical Oncology at the University of Washington and Fred Hutchinson Cancer Center, will provide strategies for leveraging BCMA-directed therapies for improved patient outcomes in relapsed/refractory multiple myeloma.
TARGET AUDIENCE
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with multiple myeloma (MM).
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to:
Evaluate the mechanisms of action, efficacy, and safety of BCMA-directed therapies in relapsed/refractory MM
Assess guideline-recommended combination and sequential treatment strategies for relapsed/refractory MM
Identify risk factors for the development of treatment-specific adverse events with different classes of BCMA-directed therapies
Describe mechanisms of drug resistance/loss of response to BCMA-directed therapies
Examine the roles of gene expression profiling, soluble BCMA, and measurable residual disease (MRD) in clinical practice.
Optimizing Treatment Sequencing for Patients With Relapsed/ Refractory Multi...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Shaji Kumar, MD, Professor of Hematological Malignancies
Mayo Clinic Cancer Center, offers expert insight on the assessment of MM, emerging and current therapies, cutting edge approaches to personalized treatments plans, and much more.
Thalassemia in Laos: Situation Analysis by Dr. Sourideth Sengchanh, Dr. Alongkone Phengsavanh, Assoc. Prof. Dr. Khampe Phongsavat, University of Health Sciences, Vientiane, Laos. Presented by Assoc. Prof. Dr. Khampe Phongsavat.
Indication of Splenectomy in child and precautions post surgery.
As some patient with high risk of infection due to splenectomy, this is some explanations about the consideration in some cases for splenectomy.
حمزة الحرايزة
جامعة العلوم والتكنولوجيا الاردنية - اربد
كلية التمريض..قسم تمريض صحة الاطفال
مناقشة مرض الثلاسيميا والانيميا
اعداد حمزة الحرايزة
الدكتورة هدى غرايبة
An excellent ppt on basics of bone marrow morphology and examination which i came accross on the internet.. Not my creation.. Full credit to the author..
Present and Future Impact of Cytogenetics on Acute Myeloid Leukemialarriva
Cytogenetics is an advancement in which clinicians can look for specific genetic mutations of chromosomal DNA and use that information to determine patient prognosis and individualize therapy. In this presentation I cover what cytogenetics are, how they impact patient risk, what therapies to use based on risk, and how genetically targeted agents may be used in the future.
Ohio State's 2016 ASH Review Blood and Marrow Trasplantation (with Turning Po...OSUCCC - James
Ohio State’s 2016 ASH Review
Blood and Marrow Transplantation
Basem M. William, MD, MRCP(UK), FACP
Assistant Professor of Internal Medicine
Blood and Marrow Transplant Program
Hemophagocytic Lymphohistiocytosis (HLH) is an aggressive and life threatening syndrome which results from excessive immune activation, that can rapidly deteriorate and lead to multiple organ failure and death.
Newer biomarkers,techniques & their inclusion in 2016 WHO classification for leukaemia/lymphomas increases the responsibility of the pathologists, requiring to develop an integrated multidisciplinary approach for reporting.
FACTORS AFFECTING INITIAL CYCLOSPORINE A LEVEL AND ITS CORRELATION WITH CLINI...Alok Gupta
FACTORS AFFECTING INITIAL CYCLOSPORINE A LEVEL AND ITS CORRELATION WITH CLINICAL OUTCOME IN ACUTE LEUKEMIA PATIENTS UNDERGOING ALLOGENEIC STEM CELL TRANSPLANTATION
The Indian economy is classified into different sectors to simplify the analysis and understanding of economic activities. For Class 10, it's essential to grasp the sectors of the Indian economy, understand their characteristics, and recognize their importance. This guide will provide detailed notes on the Sectors of the Indian Economy Class 10, using specific long-tail keywords to enhance comprehension.
For more information, visit-www.vavaclasses.com
The Art Pastor's Guide to Sabbath | Steve ThomasonSteve Thomason
What is the purpose of the Sabbath Law in the Torah. It is interesting to compare how the context of the law shifts from Exodus to Deuteronomy. Who gets to rest, and why?
How to Make a Field invisible in Odoo 17Celine George
It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
How to Split Bills in the Odoo 17 POS ModuleCeline George
Bills have a main role in point of sale procedure. It will help to track sales, handling payments and giving receipts to customers. Bill splitting also has an important role in POS. For example, If some friends come together for dinner and if they want to divide the bill then it is possible by POS bill splitting. This slide will show how to split bills in odoo 17 POS.
Unit 8 - Information and Communication Technology (Paper I).pdfThiyagu K
This slides describes the basic concepts of ICT, basics of Email, Emerging Technology and Digital Initiatives in Education. This presentations aligns with the UGC Paper I syllabus.
Instructions for Submissions thorugh G- Classroom.pptxJheel Barad
This presentation provides a briefing on how to upload submissions and documents in Google Classroom. It was prepared as part of an orientation for new Sainik School in-service teacher trainees. As a training officer, my goal is to ensure that you are comfortable and proficient with this essential tool for managing assignments and fostering student engagement.
We all have good and bad thoughts from time to time and situation to situation. We are bombarded daily with spiraling thoughts(both negative and positive) creating all-consuming feel , making us difficult to manage with associated suffering. Good thoughts are like our Mob Signal (Positive thought) amidst noise(negative thought) in the atmosphere. Negative thoughts like noise outweigh positive thoughts. These thoughts often create unwanted confusion, trouble, stress and frustration in our mind as well as chaos in our physical world. Negative thoughts are also known as “distorted thinking”.
Thalassemia Transplant Update. Dr. Suradej Hongeng
1. SURADEJ HONGENG, MD
Bangkok, Thailand
• Consultant, Department of Pediatrics at Ramathibodi
Hospital, Siriraj Hospital, Bangkok, Thailand
• Dr. Suradej Hongeng is the principal investigator for several
grants including: Frequency of thiopurine s-
methyltransferase (TPMT) genetic mutation polymorphism
in Thai children with acute leukemia; Novel gene/genes
expression in meningioma progression by representational
differential analysis cDNA (RDA cDNA).
2. Can All Thalassemia Patients Be Cured
with HSCT ?
Suradej Hongeng, MD
Ramathibodi Hospital, Mahidol University
Bangkok, Thailand
4. Treatments for Severe Thalassemia
Palliative treatment
Blood transfusion
Iron chelation
Splenectomy
Curative treatment
Hematopoietic stem cell transplant (HSCT)
Allogeneic HSC
Gene therapy
Autologous HSC
5. BMT in Thalassemia and Lucarelli Classification
Risk factors for BMT in thalassemia
Chelation Regular vs Irregular
Hepatomegaly Absent vs Present
Liver fibrosis Absent vs Present
Risk classes for BMT in thalassemia
Chelation Hepatomegaly Fibrosis
Class1 Regular NO NO
Class2 Reg/Irreg NO/YES NO/YES
Class3 Irregular YES YES
Lucarelli G et al. N Engl J Med 1990
9. HSCT in Thalassemia at Ramathibodi
Related n=28, Unrelated n=21 Total 49 patients
Overall survival (OS) and thalassemia free survival (TFS) in Thai children
Hongeng S et al. Biol Blood Marrow Transplant 2006
82%
71%
92%
82%
13. New Stratification for
High Risk Class 3 Patients
Definition
Older patients
Age > 10 yrs
Hepatomegaly
Liver > 3 cms below right costal margin
14. High Risk Class 3 Patients
(Age > 10 yrs)
Pretransplant Management Program
Hypertransfusion in order to decrease erythroid
expansion especially to decrease spleen size
Regular iron chelation for at least 6-12 months
Hydroxyurea (Hb F enhancer) in order to decrease
erythroid expansion: 20 mg/kg/day for at least
6-12 months
Sodani P et al. Blood 2004
Hongeng S et al. Am J Hematol 2007
16. 2 Iannone R, et al. BBMT 2003
3 Horan JT, et al. BMT 2005
4 Jacobsohn DA, et al. Lancet 2004
5 Krishnamurti L, et al. BMT 2006
Am J Hematol, 2007
17. Suradej Hongeng, MD
Dept of Pediatrics, Faculty of Medicine
Ramathibodi Hospital, Mahidol University
Bangkok, Thailand
Outcomes of Thalassemia Patients Undergoing
Hematopoietic Stem Cell Transplant by Using
a Standard Myeloablative (MAC) Versus
a Novel Reduced Toxicity (RTC) Conditioning
Regimen According to a New Risk Stratification
18. Novel Approach for High Risk Class 3 Patients
Pre transplant management
Hypertransfusion, chelation and hydroxyurea
Pretransplant immunosuppression (PTIS)
Flu + Dex (2 cycles)
Conditioning regimen
Bu + Flu + ATG
25. MAC Regimens and GVHD Prophylaxis
Related donor and age < 10 yrs
MAC regimen: Cyclo 200 mg/kg, Bu 14-16 mg/kg PO/IV
CSA + MTX
Unrelated group and < 10 yrs
MAC regimen: Cyclo 200 mg/kg, Bu 14-16 mg/kg PO/IV,
Flu 210 mg/m2 and ATG (Fresenius) 40 mg/kg
FK506 + MTX
27. Study Population
120 thalassemia patients undergoing HSCT; 1989 – mid 2014
(Current number 140 pts)
Exclude cord blood transplant n = 7
Exclude previous RTC transplant n = 8
(Am J Hematol; 2007)
Exclude haploidentical transplant n = 7
Final number of patients n = 98 patients
Related n = 65; Unrelated n = 33
MAC n = 76; Novel RTC n = 22
28. Patient Characteristics
MAC
Related n= 50 , Unrelated n=26 (34%)
Mismatched HLA (1 Ag or 1 Allele) 12/76 (15%)
Novel RTC
Related n=15 , Unrelated n=7 (32%)
Mismatched HLA (1 Ag or 1 Allele) 5/22 (22%)
All received BM or PBSC.
29. Novel RTC Group
22 patients
2 out of 22 had second HSCT and 1 had third HSCT
Age; median = 16 (10-21) y/o
Male 8; Female 14
Splenectomy = 7 (Referral hospital)
All patients had liver > 5 cm below costal margin.
Ferritin level; median = 3100 (869-8350) ng/mL
Comorbidities
2 DM, 1 previous extramedullary hemopoiesis,
1 previous history of PHT
30. Novel RTC Group
21 patients received PBSC.
1 patient received BM.
Median CD34+ 9.4 (4.67-19.26) x106
cells/kg
MRD 13 MMRD 2 (DRB1)
MUD 4 MMUD 2 (C) MMUD 1 (A)
38. Haplo-HSCT for Sickle Cell Disease
with Cy-Post HSCT
Bolanos-Meade et al, Blood 2012
39. Haplo-HSCT for Sickle Cell Disease with
Cy-Post HSCT
Six of 14 pts (40%) had graft failure.
Two of 14 pts could not stop IS.
Six of 14 (42%) pts were transfusion free and off IS.
40. Haploidentical Hematopoietic Stem Cell
Transplantation (Haplo-HSCT) with Pre-transplant
Immunosuppression (PTIS) Followed by
Reduced-Toxicity Conditioning (RTC) Regimen and
Post-Transplant Cyclophosphamide in Severe
Thalassemia Patients
41.
42. Patients
Jan 2013 – Dec 2014
17 patients; 9 male : 8 female
Age 2-20; 11 pts age > 10 yrs
1 pt underwent Haplo-HSCT for 2nd
Tx
43. Results
Fifteen of 17 pts survived full donor chimersim.
Median time of neutrophil engraftment = d+14
GVHD I = 6
GVHD II = 1
GVHD III = 3
Two of 15 had graft failure.
Both 2 pts received additional HSC with minimal conditioning
regimen.
One had engraftment but died of GVHD and multiorgan failure
and 1 had autologous recovery.
Three pts had anti HLA antibody and 2 of 3 pts had graft
failure.
49. Overview of the clinical protocol
Testing
and Release
While Frozen
Maximize
% Transduced
HSCs
Vector
+
Cytokines
Bone Marrow
Harvest
IV Infusion
Transduced Cells
(> 4x106
CD34+
/Kg)
(Spontaneous Homing)
CD34+ cells
(2x108
unsorted BM cells/Kg
kept for rescue)
50. 50
Initial results from the Northstar Study (HGB-204):
A Phase 1/2 Study of Gene Therapy for
β Thalassemia Major via Transplantation of‑
Autologous Hematopoietic Stem Cells Transduced
Ex-Vivo with a Lentiviral βA T87Q‑
Globin Vector‑
Alexis A. Thompson, John E. J. Rasko, Suradej Hongeng, Janet L.
Kwiatkowski, Gary Schiller, Christof von Kalle, Marina Cavazzana,
Philippe Leboulch, Alexandria Petrusich, Sandeep Soni, Mark C.
Walters
Abstract # 549
51. 5151
Subject and Cellular Product Characteristics
Subject
Number
Age Sex Genotype
Birth
Country
Splenectomy
Transfusion
Requirementa
VCN in
Cellular
Product b
CD34+
Cell
Dose (x
106
/kg)
1102 18 F β0
/βE USA Yes 137 1.0/1.1 6.5
1104 21 F β0
/βE Thailand No 153 0.7/0.7 5.4
1106 20 F β0
/β0 Pakistan No 197 1.5 13.5
1107 26 F β0
/β0 Australia No 223 1.0 15.0
1108 18 F β0
/β+ USA Yes 144 0.9 7.9
1109 29 M β0
/Ac USA Yes 158 0.6/0.6 10.1
1110 33 F β0
/β0 USA Yes 172 0.7 6.3
a
mean pRBC requirement in cc/kg/year, over the 2 years prior to consent
b
VCN= mean number of vector copies per CD34+ cell
c
Subject 1109 has alpha gene triplication, resulting in an autosomal dominant beta thalassemia phenotype.
52. 5252
Clinical Safety for Infused Subjects
52
Subject 1102 Subject 1106 Subject 1104 Subject 1107
Follow up period 6 months 3 months 2 months 1 month
Neutrophil
engraftment
ANC > 500/µL
Day +17 Day +29 Day +18 Day +14
Platelet engraftment
Unsupported platelet count
> 20,000/µL
Day +28 Day +30 Day +31 Day +27
Non-laboratory
≥Grade 3 AEs
• Mucositis
• Bacteremia
• Febrile
neutropenia
• Mucositis
• Epistaxis
• Febrile
neutropenia
• Mucositis • Mucositis
• Infection
• Headache
SAEs post-infusion None None Catheter
Thrombosis
None
• All AEs consistent with myeloablative conditioning
• No ≥Grade 3 AEs related to drug product, no RCL at 3 and 6 months
As of 21 November 2014
Subject 1108 was infused 06Nov2014 and no data is available
53. 5353
Integration Site Analysis: Subject 1102 at
Month 3
• 2393 unique gene-marked
clones identified
• No clonal dominance
observed
• Top 10 clones combined
represent 12.4% of all
clones detected
• Early polyclonal
repopulation
54. 5454
HbAT87Q
(g/dL)
VCN and HbAT87Q
in Peripheral Blood
Months post drug product infusion
Months post-drug product infusion
Drug Product VCN
β0
/β0
β0
/βE
0
0.5
1.5
1.0
1 32 60 4 5
1 32 60 4 5
β0
/β0
β0
/βE
0
2
4
6
55. 55
1
55
Hemoglobin Fractions in Whole Blood
• Subject 1102 (β0
/βE
) producing 3.8 g/dL HbAT87Q
at 6 Months
• Subject 1106 (β0
/β0
) producing 6.8 g/dL HbAT87Q
at 3 Months
Hb(g/dL)
HbAT87Q
Hb A2
Hb F
Hb E
Hb A
10.2 10.1
8.6 8.6
8.4
9.8
Subject1102Subject1106
9.6
1 32 6
Months post-drug product infusion
56. Conclusion
Outcomes of HSCT for thal in MRD, MUD and Haplo are
favorable.
Outcomes of HSCT for all age group among thal pts are
also favorable.
Whether the novel RTC regimen should be studied in
younger thalassemia patients is needed to be
investigated.
Autologous HSC with gene addition may give a new
hope for cure for thal patients.
HF information helps the registry to calculate the probability of finding a matched donor for patients. Many studies have shown that continued recruitment of random volunteers will increase the matched probability.
Moreover, calculation of the percentage of patients for whom the donor was found was performed to evaluate unrelated donor search outcome. This figure show the percentage of patients who found matched donor when registry was grown up each year.
Comparing the percentage of patients for whom the donor was found in the TSCDR with previous calculation other registries containing
a pool of 10,000–23,000 donors, a potential HLA-A, -B,
-DR serological split antigen matched donor was found in the
TSCDR (49%), higher than the Korean Marrow Donor Program
(28%) and the Europdonor Foundation (20%).
We proposed sequential pretransplant immunosuppression, consists of fludarabine 40mg/squaremeter and dexamethasone 25 mg/squaremeter for 5 days, 28-day cylcle prior to conditioning regimen.
This graph showdecreased CD4 cell prolifereation in all three representative patients.
In the past, conditioning regimen for patients older than 10 y/o was a combination of cyclophosphamide and busulfan, which is too much alkylating agent and too toxic, therefor novel approach need to be explored
Conditioning regimen comprised of 6-day of fludarabine, 4-day of busulfex and 3-day of antithymocyte globulin.
Total eighteen patients were included in this study, two of them were second transplant. Four patients with homozygous beta thalassemia with median age at 14 y/o, seven of them were male and seven patients were undergone splenectomy. All patients had hepatomegaly, with high serum ferritin level.
Most of them received peripheral blood stem cells, at median CD34 positive 9.4 million cell per kilogram. 11 of them were matched related donor.
On behalf of my clinical and research colleagues, I am pleased to present the initial results of the Northstar Study, also called HGB 204, which is a Phase 1-2 gene therapy study using autologous hematopoietic stem cell and ex vivo transduction of a lentiviral vector containing the human Beta globin gene in patients with beta thalassemia
This slides shows the characteristics of the demographic and the cellular product characteristics in Northstar subjects for whom transduction is complete
The following slides will present data focused on those subjects who have undergone stem cell infusion
Polyclonal repopulation - 2393 unique gene-marked clones identified in peripheral blood leukocytes
No clonal dominance observed - the top 10 clones combined represent 12.4% of all clones detected
