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Pre BMT Assessment for BTM

Pre BMT Assessment for BTM. Presenter: Budoor AL Emadi Intern-House Officer. Introduction. The only available alternative therapy is hematopoietic stem cell transplantation

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Pre BMT Assessment for BTM

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  1. Pre BMT Assessment for BTM Presenter: Budoor AL Emadi Intern-House Officer

  2. Introduction • The only available alternative therapy is hematopoietic stem cell transplantation • The main purpose of pre-transplant evaluation is assessment of the patient’s risk which is an important determinant of outcome podt BMT. • Besides, all the possible consequences of chronic transfusional therapy should be evaluated prior to transplantation

  3. Pre BMT Assessment in BTM • HLA Typing • Donor (Related Vs Unrelated) • HLA-DPB1 Disparity Role • Predictive Variables • Pesaro Classification • Type of Transplant • Liver Assessment • Spleen Assessment • Cardiac Assessment • Eneocrine Assessment • Hematological Assessment • Role of sICAM-1 • Dental Assessment • Pulmonary Assessment • Educating the patient • Respecting the patient autonomy

  4. HLA Typing • Because of the enormous diversity and polymorphism of the HLA; parents and siblings of the patient’s immediate family should be typed for both Class I antigens (HLA-A, B & C locus) and Class II antigens (HLA-DR & DQ). • Class I antigens are identified by an exteneded battery of tissue typing reagents (currently over 60 can be defined by serology) • Class II antigens are identified by DNA-based typing procedures then amplified by PCR. • Interestingly, these high resolution DNA typing methods have been shown to better predict GVHD and transplant outcome as compared to others. • So, the best way to prevent rejection and GVHD is to ensure that the donor and the recipient have the same types of HLA molecules.

  5. HLA Typing-cont. • Recent studies have shown that HLA-A, HLA-B, HLA-C molecules of the donor are more likely to cause rejection than HLA-DR, HLA-DQ molecules. • Recent studies have shown that HLA-DR, HLA-DQ molecules of the recipient are more likely to cause GVHD than HLA-A, HLA-B, HLA-C molecules. • In the past, it was mandatory that the donor & the recipient be perfect HLA genotypic match; however, there is growing evidence that a sibling, parent, or unrelated individual with a single major HLA-A,B, or DR mismatch can be a suitable BMT w/o necessarily conferring an increased risk for severe GVHD

  6. Donors • Donors • To find related HLA related identical donor, the most serious limitation. • Mismatched related donors (the use of HLA phenotypically (Haplotype) matched with non-idnetical family members donors at one or more antigens) • End Result, mismatched related donor transplant is not a recommended option at present in the early management of patients who can obtain and tolerate optimal medical therapy. • For those patients who cannot avail themselves of optimal medical treatment, the decision to undergo HLA nonidentical, related donor transplant should be made on the basis of the risk/benefit ratio for the individual patient and the degree of HLA disparity.In brief, results have not been rewarding and it is not a recommended option.

  7. Unrelated Donor • Matched unrelated donors • High degree of compatibility between the patient and potential donor are required. The clinical trial requires extended haplotype identity, which means identity from locus HLA-A to locus HLA-Dq on the same chromosome. • Molecular typing, along with extended matching to the HLA-DPB1 locus, has improved the outcomes with this type of transplantation.

  8. Unrelated Donor • The survival & thalassemia-free survival in HLA matched of unrelated donors Study: • -n= 68 patients -Range= 2-37 yrs -median age= 15 yrs -median F/U=40 mths (3.3 yrs) • -OS & DFS 79% and 65% respectively which is almost similar to those obtained with sibling BMT

  9. Unrelated Donor • Honeng et al (2006) stated that analysis of engraftment, frequency procedure-related complications, and thalassemia free survival showed no advantage from use of related odnor stem cells. The 2-year thalassemia-free survival estimate for recipients of related-donor stem cells was 82% compared with 71% in the unrelated-donor stem cells (p= 0.42).

  10. Role of HLA-DPB1 • -Unrelated Donor (UD) and HLA-DPB1 Disparity Role • The success of allogeneic hematopoietic stem cell transplantation (HSCT) from matched unrelated donors (UDs) for beta-thalassemia may be hampered by the occurrence of graft rejection. • The study showed that the rate of this complication can be reduced by selecting 5-loci HLA-matched donors without non-permissive mismatches at HLA-DPB1.

  11. Role of HLA-DPB1 • N= 72 beta-thalassemia, given a transplant from a UD. • N= 21 donor-recipient pairs (29%), both HLA-DPB1 alleles were matched. • The remaining pairs had one or 2 HLA-DPB1 disparities, which were classified as permissive (24 pairs, 33%) or nonpermissive in HvG (17 pairs, 24%) or GvH (10 pairs, 14%) • HLA-DPB1 alleles were classified into 3 groups with • high (group 1: DPB1*0901; *1001; *1701) immunogenicity • intermediate (group 2: DPB1*0301; *1401; *4501) immunogenicity • low (group 3: all other DPB1 alleles identified in these pairs) immunogenicity

  12. Role of HLA-DPB1 • An HLA-DPB1 mismatch was considered as permissive when the 2 mismatched alleles belonged to the same immunogenicity group. • A nonpermissive HLA-DPB1 disparity in HvG direction was assigned when the donor's allele belonged to a higher immunogenicity group as compared to the patient's allele. • An HLA-DPB1 mismatch was defined as nonpermissive in GvH direction when the patient's allele belonged to a higher immunogenicity group as compared to the donor's allele.

  13. Role of HLA-DPB1 • Results • Association of nonpermissive HLA-DPB1 disparities with graft rejection • Overall, the cumulative incidence of rejection in the HLA-DPB1 matched or permissively mismatched group was 7% (95% CI, 2-26). • The overall cumulative incidence of rejection in non-permissive HLA-DPB1 mismatches was 19% (95% CI, 9-43). • The comparison of the cumulative incidence of graft rejection between patients given transplants from donors with mismatch in HvG direction and patients receiving transplants from matched or permissively mismatched UDs is statistically significant (P < .05). • In both univariate and multivariate analysis, only the presence of disparity in HvG direction was statistically associated with the occurrence of graft rejection. • No other factor influenced the risk of graft rejection.

  14. Role of HLA-DPB1 • Association of non-permissive HLA-DPB1 disparities with aGvHD grade II-IV • The overall cumulative incidence of grade II-IV aGvHD in HLA-DPB1 allele matched or permissively mismatched group was 31% (95% CI, 20-49). • The cumulative incidence of grade II-IV aGvHD in the non-permissive groups was slightly higher (46%; 95%CI = 24-65) as compared to patients belonging to the HLA-DPB1 allele-matched or permissively mismatched group, but this difference was not statistically significant. • Association of non-permissive HLA-DPB1 mismatches with TFS and OS • TFS was reduced in patients with non-permissive HLA-DPB1 mismatches in HvG (10 of 17; 59%) or GvH (6 of 10; 60%) direction, as compared to the matched or permissive group (35 of 45; 78%). • The difference in terms of Kaplan-Meier estimates of TFS for the 3 subgroups was, however, not statistically significant. • No statistically significant association was observed between non-permissive HLA-DPB1 mismatches in either HvG or GvH direction and the rate of OS.

  15. Role of HLA-DPB1 • In multivariate analysis, HLA-DP disparity in HvG direction was associated with a statistically significant, lower probability of TFS as compared to patients belonging to the matched or permissive group (RR = 5.15; 95% CI = 1.58-16.82; P = .01). • Donor age older than 35 years was also associated with a statistically significant, lower probability of being alive and transfusion independent (RR = 3.21; 95% CI = 1.05-9.83; P = .01). • No other variable statistically influenced the probability of TFS, although there was a trend for a greater risk of treatment failure in men as compared to women.

  16. Role of HLA-DPB1 • The results of this study indicate that the risk of rejection might be reduced to low levels, comparable with those of HLA-identical sibling transplantation, by selecting UDs according to stringent rules of immunogenetics. In particular, for reaching this objective, UDs matched at the allelic level for HLA-A, -B, -C, -DRB, and -DQB1 loci should not present non-permissive mismatches at HLA-DPB1 in the HvG direction. • Another intriguing observation is that the impact of nonpermissive HLA-DPB1 mismatches on rejection is similar to that correlated to the presence of class I disparities at the allelic level in pairs matched or permissively mismatched at the HLA-DPB1 locus. • In the present study, in multivariate analysis, we found a statistically significant greater risk of treatment failure in the presence of nonpermissive HLA-DPB1 mismatches as compared to the HLA-DP matched or permissive mismatched group. The detrimental effect played by an advanced donor age on posttransplantation outcome found in our study is in agreement with a previously published analysis on around 7000 allografts from unrelated volunteers facilitated by the National Marrow Donor Program, which showed that the use of younger donors improved survival.

  17. Pesaro Classification • Three factors have been identified as variables significantly influencing transplant outcome: • 1-Hepatomegaly: defined in terms of centimeters below the costal arch • 2-Hepatic Cirrhosis: absent or present • 3-Quality of Chelation Therapy: It was characterized as regular when deferoxamine therapy was initiated not later than 18 months after the first transfusion and administered subcutaneously for eight to ten hours continuously for at least five days each week for the rest of the patient's life. Chelation therapy was defined as irregular for any deviation from this regimen.

  18. Pesaro Classification • Updated Pesaro results-From December 17, 1981 through February 28,1997, 785 consecutive patients with homozygous beta thalassemia received marrow transplants from HLA-identical related donors (761 siblings, 24 parents). The mean age was 10 ± 6 years; class distribution according to age. The conditioning regimen consisted of busulfan (14 mg/kg) and cyclophosphamide (200 mg/kg); cyclosporine alone was given for graft-versus-host disease prophylaxis.

  19. Pesaro Classification Table: Predictive variables of outcome after BMT in patients with beta thalassemia

  20. Pesaro Classification Table: Pre-transplant risk class and outcome in patients with beta thalassemia: Pesaro experience Outcome according to the class at the time of BMT from HLA-identical donors from 17, Dec, 1981 to 28, Feb, 1997 33 *Values expressed in percent Among children in class 3, the incidence of recurrent thalassemia varied from 13 percent in those who received a full dose of cyclophosphamide (200 mg/kg) to 35 percent in those who received a lower dose (120 to 160 mg/kg) combined with busulfan (14mg/kg) ^

  21. Pesaro Classification Figure (1): The overall Kaplan-Meier probability of survival and thalassemia-free survival at 16 years were 78 and 71 percent, respectively

  22. Type of TransplantTehran University Study • Type of Transplant • Shariaty Hosptal, Tehran University of Medical Sciences, between June 1990 December 2000 in Hematolgy –Oncollogy-BMT Research Cnetre • -n= 103 patients, 14 died before 3 mth, and 89 stayed alife beyond 3 mth • -recipient median age= 5.5 yrs (range 2.5-17 yrs) 47 male recipients and 42 female recipients • -donor median age= 10 yrs (range 2.5-28 yrs) 39 male donors, 50 female donors • -donor: recipient mismatch in 43 cases. • -All patients were observed until death, relapse, 2nd BMT or occurance of GVHD for a minimum of year.

  23. Type of TransplantTehran University Study • In univariate analysis, the most important risk factor for cGVHD after HLA idnetical sibling marrow transplantation was the type of the transplant. • 78.9% (15/19) of patients who underwent PBSCT developed cGVHD compared with only 34.3% (24/70) of those who underwent BMT. (RR= 3.65 p< 0.001). • -For clinical extensive cGVHD, the hazard of being developing with one year was 17.9 times higher among PBSCT than BMT. • -However, there was no difference in the probability of survival between PBSCT vs BMT (94% vs 92% p=0.6)

  24. Type of TransplantTehran University Study • Other facotrs were investigated I the study: • Prior acute cGVHD in patients with grade I, II, III, IV (RR=3.2 p=0.05), the probabilities of cGVHD in grade I, II, III, IV were 17.6%, 36.4%, 46.4%, and 68.2% respectively. • There was an incremental an incremental risk of developing cGVHD in patient with grade III, IV compared with grade 0 of aGVHD, but no significance was seen in grade I and II. • Increasing age, presence of portal fibrosis and increasing serum ferritin were significantly associated with reduced probability of survival (P= 0.0047, P= 0.016 AND P= 0.024, respectively) • -the study showed the benefit of transplanting more than 5.5 x 10 (8)/kg cells in this group of patients with no increase in complications.

  25. Liver Assessment • The Fibroscan has the potential to substitute for liver biopsy in diagnosing cirrhosis, but its utility in this disease setting has not yet been adequately tested. • So, all patients are subjected to liver biopsy Except: • -Thalassemic patients aged three years or less do not undergo routine liver biopsy and risk class is assessed on the basis of only 2 criteria • Three issues to be assessed in the liver: • 1-Fibrosis • 2-Iron deposition • 3-Chronic hepatitis

  26. Liver Assessment • Risk of nonfatal bleeding from this procedure is: • -0.5% w/o U/S guidance • -Less than 1% with U/S guidance • Things to consider in liver assessment: • Satge A cirrhosis (compensated) is not a CI for to allogenic HSCT • Seropositivity for Hepatits B & C is not a CI for to allogenic HSCT, nevertheless, serologic tests for these infections should be performed

  27. Liver Assessment • Modified Child-Pugh classification of the severity of liver disease according to the degree of ascites, the plasma concentrations of bilirubin and albumin, the prothrombin time, and the degree of encephalopathy. • -Total score of 5-6 is grade A (well-compensated disease) • -Total score of 7-9 is grade B (significant functional compromise) • -Total score of 10-15 is grade C (decompensated disease) • These grades correlate with one- and two-year patient survival: • -Grade A - 100 and 85 percent • -Grade B - 80 and 60 percent • -Grade C - 45 and 35 percent

  28. Spleen Assessment • Many thalassemic patients have splenomegaly. • Hypersplenism can complicate the posttransplant course by: • -Increasing the duration of cytpopaenia • -Increasing the need for platelet and blood transfusion • Pretransplant splenectomy should be considered in patients with severe splenomegaly. • -Severe splenomegaly: spleen extending to or below the transverse umbilical line • -Streptococus Pneumonia & Niesseria should be recommended if splenectomy is to be performed

  29. Spleen Assessment • Abstract: Impact of pretransplant splenectomy in patients with BTM undergoing BMT • The outcome of these 29 transplants was compared with 76 transplants in class III who did not have a splenectomy. • Patients in the splenectomy group were older (11.7 ± 5.0 vs. 8.5 ± 3.5 yr; p = 0.003) and had a larger liver size (5.7 ± 1.8 vs. 4.4 ± 1.6 cm; p = 0.000). • RESULTS • Splenectomized patients had a significantly faster time to ANC >500/mm3 (15.4 ± 5.9 vs. 17.5 ± 4 days; p = 0.002) and platelet >20 000/mm3 (22.5 ± 6.7 vs. 32.5 ± 13.6 days; p = 0.000). • The splenectomized group had a significantly reduced requirement of blood transfusion in the first 100 days post-transplant (5.5 ± 5.1 vs. 7.2 ± 5.4 units; p = 0.017).

  30. Spleen Assessment • There were significantly more deaths related to peri-transplant infections in the post-splenectomy group (24% vs. 5.3%; p = 0.0001). T • The graft rejections were comparable between the two groups (20.7% vs. 14.5%; p = 0.55). • The incidence of acute and chronic GVHD, late infections, and deaths were not significantly different between the two groups. • The five-yr EFS (31.0 ± 8.6 vs. 60.8 ± 5.98; p = 0.003) and OS (39.7 ± 9.3 vs. 71.8 ± 5.5; p = 0.002) was significantly worse in the splenectomized group. • CONCLUSION • In conclusion, pretransplant splenectomy among patients with β-thalassemia major was associated with faster engraftment, reduced transfusion support, a higher incidence of peri-transplant infection related deaths, and a reduced EFS and OS.

  31. Cardiac Assessment • It includes: • -12 lead ECG • -24 hour Holter monitor • -Resting Echocardiogram • -Cardiac T2 MRI to detect iron deposition in the heart • -Low dose doputamine stress echocardiography to detect reduction in cardiac contractility in asymptomatic patients • Things to consider in cardiac assessment: • -These early alterations do not have a statistically significant influence on transplant outcome • -Previous episode of HF does not represent a CI to HSCT

  32. Endocrine Assessment • A complete endocrine evaluation should be performed in patients older than 10 years of age to detect possible deficiencies induced by iron deposition in the pituitary, thyroid, and pancreas. • This includes: • -Thyroid function tests • -Growth hormone releasing hormone stimulation test for hypothalamic-anterior pituitary function • -Fasting blood glucose • -Sperm bank storage is recommended in male patients with normal semen analyses

  33. Hematological Assessment Patient and donor hemoglobin synthesis must be studied to identify: • -The status of the patient (eg, beta (0) or beta (+) thalassemic status, presence of heterozygosity for hemoglobinopathies, etc) • -The donor (normal, thalassemia minor). • A sibling with thalassemia minor can be a bone marrow donor since the posttransplant course is similar to that from a normal donor, except for mild anemia and microcytosis.

  34. Role of sICAM-1 • Increased serum levels of circulating interceluular adhesiom molecule 1 (ICAM-1) predict the risk of graft rejection after BMT for thalassemia • What is sICAM ??? • -ICAM-1 molecule is a single chain of glycoprotein composed of 5 Ig-like extracellular domains, hydrophobic transmembrane domain and and a short cytoplasmic domain. • -ICAM-1 is expressed on many hematopoietic and non hematopoietic cell surfaces. • -ICAM-1 may be induced or up-regulated by pro-inflammatory cytokinessuch as IFN-ﻻ and IFN-α. • -Through intercellular interactions, ICAM-1 mediates granulocyte extravasation, inflammatory processes and immunologic responses.

  35. Role of sICAM-1 • To investigate whether increased levels of soluble ICAM-1 may be predictive of graft rejection, the pre-transplant serum concentrations of 27 beta thalassemic patients who rejected the graft was compared to that of 68 beta thalassemic patients who achieved sustained engraftment. • Serum Samples • Serum samples were obtained from all patients 30 (range 24–36) days before BMT. • Donors were HLA identical siblings. • The 2 populations were similar regarding liver histology as determined by liver biopsy performed prior to BMT.

  36. Role of sICAM-1 • Results • 1-Beta thalassemic patients with sustained engraftment showed significantly higher pretransplant sICAM-1 (mean= 400 ng/ml) than the marrow donors in the control group (mean= 312 ng/ml). P= 0.0001 • 2-Beta thalassemic patients who rejected the graft showed significantly higher pretransplant sICAM-1 (mean= 490 ng/ml) than those with sustained engraftment (mean= 400 ng/ml). P= 0.004 • 3-Beta thalassemic patients with early rejection (within 100 days) showed significantly higher pretransplant sICAM-1 (mean= 531 ng/ml) than those with sustained engraftment (mean= 400 ng/ml). P= 0.0001 • 4-No significant values between sICAM-1 levels of patients with late rejections and patients with sustained engraftment was found. P= 0.27

  37. Role of sICAM-1 • Result No. 1 me may be ascribed as to the recurrent allo-antigen immunological stimulation due to transfusion support in beta thalassemic patients. Therefore, high sICAM-1 levels may reflect immune activation following the transfusion as an antigenic stimulus. • Patients with sustained engraftment were more heavily transfused than patients who rejected the graft. 84% of patients with sustained engraftment had received more than 100 transfusions compared to 41% of those who rejected the graft. • Kidney Allo-graft AND BMT • The report of Oplez and Terasaki in the early 1970s, it was well known that pretransplant transfusions lead to an improvement in kidney allograft survival, probably due to the induction of a state of immune unresponsiveness.

  38. Role of sICAM-1 • It is noticeable that patients with early graft rejection had significantly higher sICAM-1 levels than patients who experienced late graft rejection. This may support a transfusion-mediated role of sICAM-1. • Some beta thalassemic patients with overstimulation of the immune system due to transfusion support become immunologically unresponsive displaying relatively low concentrations of sICAM-1. • Therefore a successful engraftment, at least for 100 days, may be achieved in these patients. • In contrast, beta thalassemic patients with pre-transplant sICAM-1 levels that exceed 550 ng/ml, are at risk of maintaining an immune system that produces unfavorable effects and are likely to have an early graft rejection.

  39. Dental Assessment • Dental evaluation and restoration to eliminate any sepsis foci • Splenectomy can complicate dental care due to increased infection risk

  40. Pulmonary assessment • Since infectious and noninfectious pulmonary complications represent important complications of BMT, some of which may have lasting effects on pulmonary function, it is recommended that every candidate for an BMT, should undergo pre-transplant pulmonary function testing for two main reasons.

  41. Pulmonary assessment • First, the pre-transplant PFT provides a baseline study as a reference for future PFTs. Without a comparison pre-transplant PFT, a significant decline of lung function after transplant may not be apparent. • Second, pre-transplant PFTs may be useful for identifying patients for whom the risk of pulmonary complications/mortality is so high that the balance of these risks against the potential benefits of transplantation needs to be seriously examined.

  42. Pulmonary assessment • Future studies of pre-transplant pulmonary function should consider the advances in HCT, so that pre-transplant PFTs will become a useful tool in pre-transplant risk assessment. • Things assessed • % of predicted FVC • FEV1/FVC ratio • % of predicted VC • % of predicted TLC • % of predicted RV • % of predicted DLCO

  43. Patient • Educating patient/ parents and respecting their autonomy

  44. END

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