Haematopoietic stem cell transplant

Question 1

CMV in HSCT

Answer 1

Background

• CMV is a beta-herpesvirus. CMV remains in human body for life. T cell mediated immunity (particularly CTL CD8+ response) is most important factor for controlling CMV replication. CD8+ cells target CMV antigens (IE-1, IE-2, pp65)
• lack of CMV CTL CD8+ response pre-disposes to CMV infection. Whereas reconstitution (rebuilding) of CMV CD8+ CTL’s post HSCT confers protection against CMV and improved outcomes.
• CMV is one of the major causes of transplant related mortality in pts undergoing allogeneic HSCT, particularly with unrelated donors. Serologic status of donor/recipient is most important risk fx for CMV disease.
• 15-30% allogeneic HSCT recipients develop late CMV infection
• CMV +ve patients/recipients have worse outcomes than CMV -ve pts. Donor status in CMV +ve pts remains contraversial.
• The mechanism by which CMV influences disease relapse after HSCT is not well understood, but may be due to activation of CTL or NK cells, which then attack malignant cells. Donor cells may reactivate against CMV infected cells of the recipient, leading to GVHD.

Donor/recipient status:

• CMV+ve recipient/patient
  
  • CMV reactivation and GVHD occurs more in R+D- (recipient CMV+ve; donor -ve). R+D- status is associated with worse overall survival and higher mortality. So, if a recipient is CMV+ve, a seropositive donor is preferred to a seronegative one.
  • R+D+ has good outcomes even with unrelated donors.
• CMV -ve recipient/patient
  
  • R-D- status confers good outcomes (seronegative donors is prefered for CMV -ve pts)
  • R-D+ CMV status confers lower overall survival. CMV +ve donors can transmit CMV to -ve recipients. 30% CMV -ve recipients develop primary CMV due to sero+ve donors.

Main risk fx for CMV infection after HSCT

• recipient/donor status (as above)
• high dose steroids
• T cell depletion
• acute and chronic GVHD
• mismatched or unrelated donors

Prevention:

• antiviral prophylaxis, GVHD prophylaxis (sirolimus) and pre-emptive therapy (ganciclovir) reduces the risk of CMV infection
• CMV is now late infection (>100days after HSCT), due to prevention therapies

Sources:

(CMV In HSCT recipients) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340426/

Question 2

HSCT in R/R disease

Answer 2

Allogeneic HSCT is virtually the only curative approach for R/R AML.

Question 3

ACUTE GVHD post AlloHSCT

Answer 3

pathophys

(1) donor T cells recognise antigen-MHC complexes of recipients dendritic cells. (2) dendritic cells derived from the HSC’s are activated (in response to bacteria, virus, cytokines), they upregulate MHC II expression, then promot T cells activation, which initiate immune responses

T cell activation mediates GVHD

Treatment

• methylpred 2mg/kg/day with very slow taper
• Azithromycin in acute GVHD post alloHSCT in mice (2015, https://www.bbmt.org/article/S1083-8791(14)00606-5/abstract): during alloHSCT, prophylactic azithro improve OS, reduces acute GVHD, improves pulmonary function, reduces T cell responses by APCs, induces T reg cells and suppresses dendritic cells

Prevention

• recommendations from 2020 summary of literatures around GVHD management in HSCT: (1) broader use of rabbit anti-T-cell globulin (ATG) for GVHD prophylaxis in MUD HSCT or matched-related alloHSCT at high risk for GVHD; (2) pts receiving matched HSCT need GVHD prophylaxis with calcinurin inhibitor + antimetabolite (i.e. ciclosporin or tacrolimus, plus MTX. Note, MTX is the preferred antimetabolite for MAC-chemo, but if contra-indicated or useing non-MAC and RIC, can use mycophenolate); (3) lower steroid doses for the management of grade 2 acute GVHD with isolated skin or upper gastrointestinal tract manifestations; (4) fluticasone, azithromycin, and montelukast should be used for bronchiolitis obliterans syndrome; (5) the addition of newer treatment options for resteroid-refractory acute and chronic GVHD;
• treatment focuses on suppressing donor T cell responses. There is the risk of disease relapse and opportunistic infections.
• macrolides have been shown to inhibit dendritic cell function (by blocking NF-KB) in mice studies, inhibiting acute GVHD (in MHC incompatible HSCT) without interfering with donor engraftment [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569542/ ; 2013]
  read: https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-grading-of-acute-graft-versus-host-disease?search=graft%20vs%20host%20disease&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Question 4

Allogeneic HSCT

Answer 4

All patients require HLA A and B typing.

Indications: R/R AML

read: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348112/ —- flu/mel conditioning for allo

Question 5

CHRONIC GVHD

Answer 5

Treament

[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(19)30256-X/fulltext?rss=yes ; also have pdf]

• prednisolone 1mg/kg
• second line agents in CGVHD esp those that are steroid refractory (often used in addition to corticosteroids): calcineurin inhibitors (tac, ciclo), ibrutinib (which is FDA approved), extracorporeal photophoresis, JAK inhibitors, mycophenolate mofetil, rituximab, mTOR inhibitors, TKI’s. But there is not data for comparison of 2nd-line options.
• 2nd line options should be used in pts with severe chronic GVHD, solely for purpose of steroid sparing. No benefit in pts of standard risk CGVHD

macrolides and chronic (C) GVHD

2019 (retrospective review of HCT database) Effect of Azithromycin on Relapse in Mod-sev CGVHD https://www.bbmt.org/article/S1083-8791(18)30919-4/abstract

• patients with mod-severe cGVHD post alloHSCT (matched related or unrelated) on extended azithromycin prophylaxis [extended time = >14days; median time on azithro was 26months for this grp; median time to start azithro was 15months post HSCT], results at 2years follow up showed reduced cumulative relapse rates (2%) vs 16% (pts not on extended azithro); improved 2year o/survivial 93% (extended azithro) vs 78% (not extended azithro).
• CONC: extended course azithro (median time ) in pts with mod-severe CGVHD following HSCT isn’t assicated w increased risk relapse, so shouldn’t be contra-indicated in this population, but additional studies are needed.
• Study limits: retrospective; most pts in group B (not on azithro) didn’t have Bronchiolitis Obliterans whereas all patients in grp A (extended azithro) did; cGVHD more common in grp A (extended azithro); ?incidence of relapse not calculated from time of azithro commecement.

Azithro for GVHD prophylaxis during HSCT

(2018 RCT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141429/)

• in pts with acute leukemia who had matched alloHSCT, there was no difference in incidence of acute or chronic GVHD in pts who received azithro during conditioning and those who didn’t.

Question 6

graft vs leukemic

Answer 6

https://www.sciencedirect.com/topics/medicine-and-dentistry/graft-versus-leukemia-effect

Question 7

autograft

Answer 7

https://www.ncbi.nlm.nih.gov/books/NBK12844/

Question 8

Stem cells

Answer 8

Hematopoietic stem cells (HSCs):

• give rise to progenitor cells of all 10 blood lineages (erythrocytes, platelets, neutrophils, eosinophils, basophils, monocytes, T and B lymphocytes, natural killer cells, and dendritic cells).
• They are in a resting or non-dividing state and have the capacity to self-renew.
• peripheral blood stem cells are the small number of stem cells that make their way from the bone marrow to the circulating blood.