DISEASE INDICATION FOR HEMATOPOIETIC STEM CELL TRANSPLATATION

1. HEMATOPOIETIC STEM
CELL TRANSPLANT IN
PEDIATRIC
DR ABHIJEET MANOHAR WANKHEDE

2. DEFINITION:
• HEMATOPOIETIC STEM CELL TRANSPLATATION INVOLVES THE INTRAVENOUS INFUSION OF
AUTOLOGOUS( FROM A DONOR) OR ALLOGENIC(FROM SAME INDIVIDUAL) STEM CELLS
COLLECTED FROM
1.BONE MARROW OR
2. PERIPHERAL BLOOD OR
3. UMBLICAL CORD
TO RE-ESTABLISH HEMATOPOIETC FUNCTION IN THE PATIENT WHOSE BONE MARROW OR IMMUNE
SYSTEM IS DAMAGED OR DEFECTIVE DUE TO MALIGNANT OR NON MALIGNANT DISORDERS

3. HISTORY
• IN 1956, THE FIRST SUCCESSFUL BONE MARROW
TRANSPLANT WAS PERFORMED BY DR E. DONNALL THOMAS
IN COOPERSTOWN, NEW YORK.
• FROM THE MID-1950S DONNALL THOMAS DEVELOPED
METHODS OF PROVIDING NEW BONE MARROW CELLS FOR
PEOPLE THROUGH TRANSPLANTS. USING RADIATION AND
CHEMOTHERAPY, THE BODY'S OWN BONE MARROW CELLS
ARE KILLED AND THE IMMUNE SYSTEM'S REJECTION
MECHANISM IS SUBDUED. BONE MARROW CELLS FROM A
DONOR ARE THEN PROVIDED THROUGH A BLOOD
TRANSFUSION.
E. Donnall Thomas

4. HEMATOPOIETIC STEM CELL
• POPULATION OF UNDIFFERENTIATEDCELLS WHICH HAVE THE ABILITY
1. TO REGENERATE
2. TO HOME TO THE MARROW SPACE FOLLOWING INTRAVENOUS INFUSION
3. TO BE CRYOPRESERVED

6. TRANSPLANTATION
• AUTOLOGOUS- PATIENT RECEIVE THEIR OWN STEM CELLS
• ALLOGENIC - PATIENT RECEIVE STEM CELLS SFROM SOMEONE OTHER THAN PATIENT OR
IDENTICAL TWIN
• SYNERGIC - PATIENT RECEIVES STEM CELLS FROM THEIR IDENTICAL TWIN

7. HSCT
AUTOLOGOUS TRANSPLANTATION
• REMOVAL AND STORAGE OF PATIENTS
OWN STEM CELLS WITH SUBSEQUENT
REINFUSIONAFTER THE PATIENT RECIEVES
HIGH DOSES MYELOABLATIVE THERAPY
• NO RISK OF GVHD
ALLOGENIC TRANSPLANTATION
• DONER AND RECEPIENT ARE
IMMUNOLOGICALLY NOT IDENTICAL.
IMMUNE CELLS TRANSPLANTED WITH THE
STEM CELLS OR DEVELOPING FROM THEM
CAN REACT AGAINST THE PATIENT
• RISK OF GVHD

8. ILLUSTRATION OF PREFERRED HSCT CELL SOURCE FOR TREATMENT OF
MALIGNANCY
MATCHED SIBLING DONOR
MATCHED UNRELATED DONOR
MISMATCHED
UNRELATED DONOR
SINGLE OR DOUBLE
UMBLICAL CORD
TRANSPLANT
HAPLOIDENTICAL
DONOR
ALGORITHM: IF A MATCHEDSIBLING DONOR IS NOT AVAILABLE, THEN MATCHED UNRELATEDDONOR(MUD) IS
SELECTED. IF MUD IS NOT AVAILABLE THEN CHOICES INCLUDE MISMATCHED UNRELATEDDONOR, UMBILICAL CORD
DONOR AND A HAPLOIDENTICAL DONOR

9. POTENTIAL STEM CELL SOURCES
• AUTOLOGOUSSTEM CELLS
• HLA MATCHED RELATED DONORS
• HLA MATCHED UNRELATED DONORS
• HAPLOIDENTICAL RELATED DONORS
• UMBLICAL CORD DONORS

10. INDICATIONS TO AUTOLOGOUS HEMATOPOIETIC
STEM CELL TRANSPLANTATION FOR PEDIATRIC
DISEASES
• ACUTE LYMPHOBLASTIC LEUKEMIA AFTER AN ISOLATED EXTRAMEDULLARY
RELAPSE
• RELAPSED HODGKIN OR NON-HODGKIN LYMPHOMA
• STAGE IV OR RELAPSED NEUROBLASTOMA
• HIGH-RISK, RELAPSED, OR RESISTANT BRAIN TUMORS
• STAGE IV EWING SARCOMA
• LIFE-THREATENING AUTOIMMUNE DISEASES RESISTANT TO CONVENTIONAL
• TREATMENTS

11. INDICATIONS FOR ALLOGENEIC HEMATOPOIETIC
STEM CELL TRANSPLANTATION FOR PEDIATRIC
DISEASES
• ACUTE MYELOID LEUKEMIA IN 1ST COMPLETE REMISSION OR IN
ADVANCED
DISEASE PHASE
• PHILADELPHIACHROMOSOME–POSITIVECHRONIC MYELOID LEUKEMIA
• MYELODYSPLASTIC SYNDROMES
• HODGKIN AND NON-HODGKIN LYMPHOMAS
• SELECTED SOLID TUMORS
• METASTATIC NEUROBLASTOMA
• RHABDOMYOSARCOMA REFRACTORY TOCONVENTIONAL TREATMENT
• VERY-HIGH-RISK EWINGSARCOMA
• SEVERE ACQUIREDAPLASTIC ANEMIA
• FANCONIANEMIA
• CONGENITAL DYSKERATOSIS
• DIAMOND-BLACKFAN ANEMIA
• THALASSEMIA MAJOR
FIRST COMPLETE REMISSION FOR
PATIENTS AT VERY HIGH RISK OF RELAPSE
TRANSLOCATION T(9;22) OR T(4;11)
• EARLY THYMOCYTE PRECURSOR PHENOTYPE
• NONRESPONDER AFTER 1 WK OF
CORTICOSTEROID THERAPY AND
• T-IMMUNOPHENOTYPE OR
• >100,000 CELLS/ΜL AT DIAGNOSIS
• NOT IN REMISSION AT THE END OF THE
INDUCTION PHASE
• MARKED HYPODIPLOIDY (<43 CHROMOSOMES)
• HIGH LEVELS OF MINIMAL RESIDUAL DISEASE AT
THE END OF INDUCTION
THERAPY
SECOND COMPLETE REMISSION THIRD OR
LATER COMPLETE REMISSION
• ACUTE LYMPHOBLASTIC LEUKEMIA

12. PROTOCOLS FOR ALLOGENEIC HSCT
• 1. PREPARATIVE REGIMEN
• 2. TRANSPLANTATION

13. PREPARATIVE REGIMEN
CHEMOTHERAPY +/- IRRADIATION F/B INFUSION OF HEMATOPOIETICCELLS
FROM THE DONOR
AIM- TO DESTROY PATIENTS HEMATOPOIETIC SYSYTEM
- TO SUPPRESS THE IMMUNE SYSTEM, ESPECIALLY T CELLS TO PREVENT GRAFT
REJECTION
IN PEDIATRIC PATIENT – Reduced Intensity
Conditioning regimens is used

14. GRAFT VS LEUKEMIA EFFECT(GVL)
• IN HSCT , IN ADDITIONTO STEM CELLS, THE GRAFT CONTAINS MATURE BLOOD CELLS OF DONOR
ORIGIN INCLUDINGT CELL , B CELL , NATURAL KILLER CELLS AND DENDRITIC CELLS
• THIS REPOPULATES/RESTORES PATIENTSRECEPIENTSLYMPHOHEMMATOPOIETTICSYSTEMTO GIVE
RISE TO A NEW IMMUNE SYSTEM
ELIMINATIONOF RESIDUAL LEUKEMICCELLS THAT SURVIVES THE CONDITIONING REGIMEN
THIS IS GVL EFFECT

15. HLA COMPATIBLE
SIBLINGS

16. FOR CHILDREN WITH
HEMATOLOGICAL MALIGNANCIES AND
CONGENITAL DISEASE-
ALLOGENIC HSCT IS THE TREATMENT OF
CHOICE

17. 1. ACUTE LYMPHOBLASTIC LEUKEMIA -
- ALL is the most common indication for HSCT in childhood, in the first complete remission
when a child
is at high risk of leukemia recurrence or in second or further complete remission
after previous marrow relapse
- Total body irradiation in
the preparative regimen has advantage in terms of better eventfree
survival compared to cytotoxic drugs alone

18. 2. ACUTE MYELOID LEUKEMIA -
- Allogeneic HSCT from an HLA-identical sibling for postremission treatment of pediatric
patients with acute myeloid
leukemia (AML)
- Allogeneic HSCT as consolidation
Therapy in Children with AML
in 1st complete remission is better than
either chemotherapy alone or with autologoustransplantation due to survival benefit
- In acute
promyelocytic leukemia in molecular remission with chemotherapy, inv 16, translocation
t(8;21) do not need Allogenic HSCT in view of excellent prognosis with other treatments
-Approximately 40% of
pediatric patients with AML in the second complete remission can be
rescued by an allograft from an HLA-identical sibling.

19. 3. CHRONIC MYELOGENOUS LEUKEMIA
- For Philadelphia positive CML only proven curative treatment is
Allogenic HSCT.
- Leukemia-free survival after an allograft is 45-80%
- Factors influencing the outcome include
Phase of disease (chronic phase, accelerated phase, blast crisis),
Recipient age
Type of donor employed (either related or unrelated), and
Time interval between diagnosis and HSCT
-Best results in chronic phase from HLA identical sibling within 1
year from diagnosis
- BCR-ABL
tyrosine protein kinase inhibitors (imatinib mesylate,
dasatinib,nilotinib), targeting the enzymatic activity of the BCR-ABL
fusion
Protein.

20. 4.JUVENILE MYELOMONOCYTIC LEUKEMIA
-Characteristics-
1.Hepatosplenomegaly
2.organ infiltration, with excessive proliferation of cells of monocytic and granulocytic
Lineages.
PATHOPHYSIOLOGY- Hypersensitivity to GM CSF AND pathologic activation of the RAS-RAF-MAP
(mitogen-activated protein) kinase signaling pathway
- For untreated patients median duration of survival is less than 12 months from the diagnosis due to its
aggressive clinical course
-HSCT is able to
cure approximately 50-60% of patients with JMML
- Recurrence is main cause of treatment failure after HSCT
- Splenectomy before transplantation can be performed, but doesnot affect the posttransplatation outcome

21. 5. MYELODYSPLASTIC SYNDROMES OTHER THAN
JUVENILE MYELOMONOCYTIC LEUKEMIA-
-Heterogeneous group of clonal disorders
-Peripheral
blood cytopenia due to ineffective hematopoiesis
- For RAEB and RAEB-t HSCT IS Treatment of choice
-For
children with refractory cytopenia, the probability of event-free survival
after HSCT may be as high as 80%

22. 6.NON-HODGKIN LYMPHOMA AND HODGKIN DISEASE
• CHILDHOOD NHL AND HODGKIN DISEASE ARE QUITE RESPONSIVE TO CONVENTIONAL
CHEMORADIOTHERAPY.
• HSCT CAN CURE A PROPORTION OF PATIENTS WITH RELAPSEDNHL AND HD.
• IF AN HLA-IDENTICALSIBLING IS AVAILABLE, ALLOGENEIC TRANSPLANTATION SHOULD BE
OFFERED TO PATIENTS WITH NHL TO TAKE ADVANTAGE OF THE GVL EFFECT.

23. 7.ACQUIRED APLASTIC ANEMIA
• HSCT FROM AN HLA-IDENTICAL SIBLING IS THE TREATMENT OF CHOICE FOR CHILDREN WITH THE SEVERE FORM OF ACQUIRED APLASTIC
ANEMIA.
• SEVERE FORM OF ACQUIRED APLASTIC ANEMIA DEFINED AS-
PLATELET COUNT <20,000/MM3
ABSOLUTE NEUTROPHIL COUNT <500/MM3 OR
RETICULOCYTE COUNT <1% WHEN ANEMIA IS PRESENT WITH HYPOPLASTIC BONE MARROW (<20% TOTAL CELLULARITY).
-GRAFT REJECTION REPRESENTS THE MOST
IMPORTANT CAUSE OF TREATMENT FAILURE.
-GVHD PROPHYLAXIS COMBINING
CYCLOSPORINE AND SHORT-TERM METHOTREXATE IS ASSOCIATED WITH A
BETTER OUTCOME AS COMPARED TO CYCLOSPORINE ALONE

24. 7. CONSTITUTIONAL APLASTIC ANEMIA
• FANCONI ANEMIA AND DYSKERATOSIS CONGENITA ARE GENETIC DISORDERS ASSOCIATED WITH A HIGH RISK OF
DEVELOPING PANCYTOPENIA
• SPONTANEOUS CHROMOSOMAL FRAGILITY INCREASED AFTER EXPOSURE OF PERIPHERAL BLOOD LYMPHOCYTES TO
DNA CROSSLINKING AGENTS, INCLUDING CLASTOGENIC COMPOUNDS, SUCH AS DIEPOXYBUTANE, MITOMYCIN C,
AND MELPHALAN.
• HSCT CAN RESCUE APLASTIC ANEMIA AND PREVENT THE OCCURRENCE OF CLONAL HEMATOPOIETIC DISORDERS
• EITHER REDUCED DOSES OF CYCLOPHOSPHAMIDE ALONE OR LOW-DOSE CYCLOPHOSPHAMIDE WITH
FLUDARABINE ARE CURRENTLY EMPLOYED FOR PREPARING FANCONI ANEMIA PATIENTS TO THE ALLOGRAFT
• THE SUCCESS RATE OF HSCT FROM AN HLA-IDENTICAL SIBLING IS ON THE ORDER OF 70-80%.
• ALLOGENEIC HSCT REMAINS THE ONLY POTENTIALLY CURATIVE APPROACH FOR SEVERE BONE MARROW FAILURE
ASSOCIATED WITH DYSKERATOSIS CONGENITA

25. 8. THALASSEMIA
• HSCT REMAINS THE ONLY CURATIVE TREATMENT FOR PATIENTS WITH THALASSEMIA
• AMONG CHILDREN,
• 3 CLASSES OF RISK HAVE BEEN IDENTIFIED ON THE BASIS OF 3PARAMETERS,NAMELY - REGULARITY OF PREVIOUS IRON CHELATION,
-LIVER ENLARGEMENT, AND
- PRESENCE OF PORTAL FIBROSIS
-AS IN OTHER NONMALIGNANT DISORDERS THE MOST EFFECTIVE PHARMACOLOGIC
COMBINATIONS (SUCH AS THAT INCLUDING CYCLOSPORINE AND
METHOTREXATE) SHOULD BE EMPLOYED TO PREVENT GVHD.
-THE OUTCOME OF
PATIENTS TRANSPLANTED FROM AN UNRELATED DONOR HAS BEEN REPORTED TO BE
SIMILAR TO THAT OF HLA-IDENTICAL SIBLING RECIPIENTS.

26. 9. SICKLE CELL DISEASE
• DESPITE THE FACT THAT HYDROXYUREA, FAVORING THE SYNTHESIS OF FETAL HEMOGLOBIN, REDUCES THE
FREQUENCY AND SEVERITY OF VASOOCCLUSIVE CRISES AND IMPROVES THE QUALITY OF LIFE FOR PATIENTS
WITH SICKLE CELL DISEASE, ALLOGENEIC HSCT IS THE ONLY CURATIVE TREATMENT FOR THIS DISEASE.
• THE MAIN INDICATIONS
• FOR PERFORMING HSCT IN PATIENTS WITH SICKLE CELL DISEASE ARE HISTORY OF STROKES, MAGNETIC
RESONANCE IMAGING OF CENTRAL NERVOUS SYSTEM LESIONS ASSOCIATED WITH IMPAIRED
NEUROPSYCHOLOGIC FUNCTION, FAILURE TO RESPOND TO HYDROXYUREA AS SHOWN BY RECURRENT ACUTE
CHEST SYNDROME, AND/OR RECURRENT VASOOCCLUSIVE CRISES AND/OR SEVERE ANEMIA AND/OR
OSTEONECROSIS
• THE USE OF ANTITHYMOCYTE GLOBULIN DURING THE PREPARATIVE REGIMEN IMPROVES PATIENT OUTCOME,
DRAMATICALLY REDUCING THE RISK OF GRAFT FAILURE.

27. CONDITIONING (PREPARATIVE) REGIMEN
• TO SUPPRESS THE PATIENT’S IMMUNE SYSTEM FROM REJECTING STEM CELLS
• TO ELIMINATE THE CANCER

28. AUTOLOGOUS BONE MARROW
TRANSPLANTATION CRITERIA
• TUMOR WITH DOSE RESPONSE CURVE
• TUMOR SENSITIVE TO MYELOSUPPRESSIVE AGENTS
• PURGING TECHNIQUES IF MARROW IS CONTAMINATED WITH TUMOR
- PRESERVE STEM CELL
- ERADICATE TUMOUR
. TECHNIQUE FOR PERIPHERAL STEM CELL COLLECTIONS
.MINIMAL TUMOR BURDEN
.MARROW ABLATION

29. RECOVERING FROM THE TRANSPLANT
• RECOVERY OF NORMAL LEVEL CELLS IS CALLED ENGRAFTMENT
• DAY 8 TO 12
• NEUTROPHIL ENGRAFTMENT IS IMPORTANT AND GCSF MAY BE GIVEN TO ACCELERATE THE
PROCESS
• PLATELETS ARE THE NEXT CELLS TO RETURN AND RED CELLS LAST
• COMMONLY PATIENT REQUIRE TRANSFUSIONOF PLATELETS AND RED CELLS FOLLOWING
TRANSPLANTS
• DISCHARGE UPON NEUTROPHIL AND PLATELET ENGRAFTMENT

30. COMPLICATIONS
ALLOGENIC (EARLY)
-INFECTION
-ACUTE GVHD
-BLEEDING
-TOXICITY
-GRAFT FAILURE
ALLOGENIC (LATE)
- CHRONIC GVHD
-INFECTION
-RELAPSE
-GONADAL FAILURE
-SECONDARY MALIGNANCY
-TOXICITY

31. COMPLICATIONS
AUTOLOGOUS (EARLY)
• INFECTION
• BLEDDING
• TOXICITY
AUTOLOGOUS (LATE)
• RELAPSE
• INFECTION
• GONADAL FAILURE
• SECONDARY MALIGNANCY
• TOXICITY

32. THANK YOU!