PTLD

Algemeen

PTLD = Posttransplant lymphoproliferative disorder.
PTLD is een potentiëel fatale ziekte na solide-orgaan transplantatie (SOT) of allogene stamceltransplantatie (SCT). Immunosuppressiva en EBV primaire infectie/reactivatie zijn belangrijke factoren in de pathogenese. Onze huidige kennis omtrent PTLD is beperkt door het lage voorkomen, morfologische en immunologische heterogeniteit en gebrek aan prospectieve studies.

Categorie PTLD

Indeling in volgende categorieën (WHO 2008):

• Early-type PTLDs: nondestructive lymphoplasmacytic proliferations. Subdivided in plasmacytic hyperplasia and infectious mononucleosis–like paracortical hyperplasia.

• Polymorphic PTLDs: destructive lymphoplasmacytic proliferations that do not fulfill the strict criteria of a malignant lymphoma.

• Monomorphic PTLDs: these lymphomas fulfill the histopathological criteria of a lymphoma recognized in immunocompetent hosts.

  • Majority is of B-cell phenotype; DLBCL, BL and plasmablastic lymphoma as most prevalent subtypes

  • Other: T-cell lymphomas (like hepatosplenic T-cell lymphoma), sporadically, classical HL.

NB. Indolente B-cell lymfomen worden niet beschouwd als PTLD, ook niet als het voorkomt in een post-transplantatie patiënt.

De exacte classificatie van PTLD is soms lastig door overlap tussen categorieën, of doordat uit verschillende biopten van verschillende lokaties een andere categorie kan laten zien. Dat laatste komt overigens ook overeen met het concept dat er progressieve transformatie van early naar polymorfe en vervolgens monomorfe PTLD plaatsvindt. Derhalve is het herhalen van een biopt laagdrempelig geïndiceerd.

Impact of transplanted organ type on PTLD

In addition to pretransplant EBV mismatch (the most important risk factor for developing PTLD) and the immune suppressive agents used to prevent rejection, the type of transplant organ also determines the risk for PTLD.

• Incidentie:

  • Haploidentical HSCT, heart/lung, and multivisceral transplants (up to 20%),

  • Followed by liver (4.5%), combination heart-lung (2.5%), pancreas (2%), kidney (1%-1.5%)

  • Matched related and unrelated HSCT (0.5%-1%).

In contrast to SOT, PTLD after HSCT is almost exclusively of donor origin and develops during the first 6 months after transplant. This unique feature is a consequence of the profound T cell–depleting conditioning regimen, leading to lack of EBV-specific T cells and, hence, the often impressive and rapid growth of an EBV⁺ clone, even within the first weeks. Because immune reconstitution occurs in the first 6 to 12 months and oral immune suppression can often be stopped, late PTLD is rare after HSCT. However, an interesting finding is the increased incidence of late-onset HL in patients undergoing HSCT. In this population, a standardized incidence ratio of 6.2 was observed, whereas a standardized incidence ratio after SOT is ∼3.7. The lack of association with low CD4 counts is in line with the observation of typically normal CD4 counts in HIV⁺ patients diagnosed with HL.

Stagering PTLD

Accurate staging and assessment of response and end-of-treatment remission are important for optimal management of patients with lymphoma. Imaging plays a major role herein, and ¹⁸F-FDG–PET/CT has become the standard to assess pretreatment evaluation and therapy response in FDG-avid lymphomas.

EBV

EBV- PTLD associatie

Ondanks sterke associatie tussen EBV en PTLD is 33-48% vd PTLD EBV negatief. EBV negatieve PTLDs komen vaker later na een transplantatie (jaren) voor dan EBV positieve PTLDs (maanden). Het is onduidelijk of deze prognose tussen beide verschilt.

EBV load voor diagnose/preventie PTLD

EBV loads worden gebruikt voor het starten van pre-emptieve therapie, waarbij immuun suppressiva worden afgebouwd en/of rituximab wordt gegeven afgaande op de EBV load (zowel in SOT als SCT patiënten).

MRD

Monomorphic PTLD heeft vaak een klonale immuunglobuline of T-cel receptor gen rearrangement in de respectievelijk B- of T cel kloon.

Behandeling Burkitt-lymfoom PTLD

BL-PTLD is a special subtype of monomorphic CD20⁺ PTLD. Guidelines on optimal treatment of BL-PTLD are lacking for several reasons.

• First, BL-PTLD is a very rare disorder that has been studied less intensively compared to other BL subtypes.

• Second, some BL-PTLD cases are MYC negative and characterized by the 11q-gain/loss pattern. Thus, the frequent lack of cytogenetic/fluorescence in situ hybridization data in published series and case reports makes distinction between true BL and BL-like cases impossible.

The main questions concerning BL-PTLD are

• Does the clinical behavior of this disorder mimic other BL subtypes?

• Does the proposed management strategy in other subtypes (ie, intensive multiagent chemotherapy, rituximab, and, in the case of HIV-associated BL, reconstitution of the immune system) also apply to patients presenting with BL-PTLD or is less-intensive treatment (rituximab and low-dose chemotherapy in combination with RIS) more desirable?

Therefore, we performed a literature search and identified 6 small case series (3 pediatric and 3 adult) focusing on treatment of BL-PTLD (n= 39, wv 90% late-onset PTLD).

• In the 3 pediatric case series, treatment ranged from RIS and low-dose immunochemotherapy (rituximab-cyclophosphamide-prednisone) to RIS and intensive BL regimens, all leading to similar long-term outcome (75%-100% long-term survivors).

• In 2 adult case series, patients were treated with RIS, followed by short intensive chemotherapeutic regimens. Although response rates were acceptable (75%), toxicity was high (3/5). In a recent case series from the German Study Group on PTLD, 5 of 8 adult patients received sequential immunochemotherapy (4 courses of rituximab followed by 4 courses of CHOP). Four of 5 patients reached complete remission, of which 1 had an early relapse. No intrathecal prophylaxis was given. The investigators concluded that sequential immunochemotherapy was a safe and effective treatment of BL-PTLD.

Prognose PTLD

De prognose van PTLD is slechter dan een DLBCL in immuun-competente patiënt

• PTLD: 5y OS 40-60%

• DLBCL afhankelijk van IPI score: 4y OS 50-90%

Risicofactoren voor slechtere uitkomst:

• klassiek: ouder, hoge stadium, slechte PS, verhoogd LDH en CNS betrokkenheid.

• Nieuwer: hypoalbuminemie.

Derhalve risicoclassificatie ook obv IPI. Daarnaast voorspelt de respons opde eerste cycli rituximab ook de OS.