Perifeer T-cel lymfoom

Peripheral T-cell non-Hodgkin lymphomas (PTCL) account for ~10% of aggressive non-Hodgkin lymphoma case. The prognosis of PTCL is unfavorable, with the remarkable exception of ALK-positive cases.

Prognosis: 5-year disease-free survival for PTCL after conventional first-line chemotherapy is ~30%. Although no prospective randomized trial was performed, prospective studies suggest, when feasible, that the use of high-dose chemotherapy (HDC) with autologous stem cell transplantation as consolidation therapy in first-line therapy can improve the survival rate to 50–60%.


Eerste lijn

Hematologie wijzer: 6 kuren CHOP à 3 weken
Ter overweging:  RT 40 Gy (20 * 2 Gy) op FDG-PET positieve laesies na chemo.

CHOP versus CHOEP
*The German high-grade non-Hodgkin lymphoma study group: als <60y and normal LDH dan betere outcome met CHOEP vs CHOP( 3-year EFS 75% vs 50%, geen verschil in OS), meest uitgesproken voor de ALKpos ALCL groep.In ouderen echter meer tox als toevoegen etoposide.
* The Nordic group: CR rate met CHOEP 51% vs 39% in ander cohort met CHOP. In de nordic group was mean age 51y.

Nieuwe overwegingen:
CHOP plus obv NGS; 

in deze studie: CR rates van 33--> 65%, ORR van 52--> 69%. Dit komt met name door de TP53 en TET2 patiënten, dus de HMT toevoegen aan CHOP lijkt het meest zinvol. 

Bij HDACi (romidepsin) + CHOP is er een negatieve trial, waarschijnlijk agv de vele onderbrekingen van de CHOP


Relapsed or refractory T-cel lymphoma 

Patients with relapsed or refractory T-cell lymphoma have a particularly bleak prognosis; they often fail to respond to further therapy. Chemotherapy regimens recommended to treat such patients have been identical to those for patients with relapsed aggressive B-cell lymphoma. Alternative cytotoxic drugs like bendamustine or pralatrexate may achieve mostly transient responses in 33-50% of patients treated. Salvage therapy is most valuable to bridge patients to transplantation.

Before assessing the role of transplantation in more detail, it is important to note that retrospective analyses of transplant outcomes are biased by the impossibility to report on patients not making it to transplantation because of relapse and refractory disease, age, frailty, toxicity of previous treatment, or lack of a suitable donor. Importantly, the few prospective studies on HDT/ASCT  and allogeneic HSCT  unanimously report that around 40% of patients could not undergo transplantation because of early progression or relapse. Thus, 25-33% of patients will never proceed to transplantation. More chemotherapy given at shorter time intervals, as with any alternative strategy, failed to change this pattern of early failure and relapse.


Salvage regimens:


Traditioneel: Conform DLBCL: ICE, DHAP, Gemcitabine (GDP, met cisplatin en dex, OF GeOx met oxali), overwegen BeGeV zie hieronder. Maar als al refractair op 1e/2e lijns chemotherapie is kans op duurzame respons op nieuwe lijn chemotherapie verwaarloosbaar.

 

Voorkeur in de 2e lijn:

Brentuximab (anti-CD30): eventueel ook als monotherapie!

Barta et al. Blood 2019: Among PTCLs, ALCLs show the most intense and uniform expression of CD30, regardless of ALK gene rearrangements.  Partial and weaker expression are found in PTCL, not otherwise specified (PTCL-NOS; 58-64%), angioimmunoblastic lymphoma (AITL; 63-75%), enteropathy-associated T-cell lymphomas (EATLs; 0-100%), human T-cell leukemia virus, type 1–associated adult T-cell leukemia/lymphomas (ATLLs; 0-55%), and extranodal natural killer/T-cell lymphomas (36-47%).

In PTCL, the levels of CD30 messenger RNA and protein are closely related. Immunohistochemistry on formalin-fixed paraffin-embedded tissue with the monoclonal antibody BerH2 is routinely used to detect CD30 expression, with a “membrane and dot/cytoplasm” staining pattern. However, there is a lack of consensus on positive cutoffs for CD30 expression. Studies have used the percentage of positive cells, staining intensity, or both to determine positive cutoff values (≥1%, ≥10%, or 20-25%) but the clinical impact of different criteria is unclear.

Brentuximab in R/R PTCL: Of 35 enrolled patients,  63% had PTCL-NOS, and 37% had AITL. The ORR for 34 evaluable patients was 41% (CR 24%); in AITL, the ORR was numerically higher at 54% (CR 38%) than in PTCL-NOS (ORR, 33%; CR, 14%). Median duration of response was 5.5 months for AITL patients and 7.6 months in PTCL-NOS. Median PFS for all patients was only 2.6 months (6.7 months for AITL; 1.6 months for PTCL-NOS). However, 10 patients (29%) had responses lasting >6 months. Treatment was discontinued for disease progression in 57% and for AEs in 20%, most frequently PSN (6%). CD30 expression did not correlate with efficacy; responses were seen in patients with ≤15% CD30 (ORR, 64%). Notably, 6 (17%) of the enrolled patients had undetectable CD30 expression by central review.

 

Nieuwer:

Bendamustine (alkylerend oncolyticum):

BENTLY trial, Damaj et al. JCO 2013

Method: bendamustine at 120 mg/m(2) per day on days 1 through 2 every 3 weeks for six cycles.

Resuls: Of the 60 patients included, 45% were refractory to their last prior chemotherapy, and the median duration of the best previous response was 6.6 months. 33% received fewer than three cycles of bendamustine, mostly because of disease progression. In the intent-to-treat population, the ORR was 50%, including CR in 28% and PR in 22%. Bendamustine showed consistent efficacy independent of major disease characteristics. The median values for DoR, PFS, and OS were 3.5, 3.6, and 6.2 months, respectively. The most frequent grade 3 to 4 adverse events were neutropenia (30%), thrombocytopenia (24%), and infections (20%).

-          Schema: BeGEV?


Pralatrexate (antifolaat): niet beschikbaar in NL.

PROPEL trial, O'Connor et al. JCO 2011

Of 115 patients enrolled, 111 were treated with pralatrexate. The median number of prior systemic therapies was 3. The response rate in 109 evaluable patients was 29%, including CR (11%), PR (18%), with a median DoR of 10.1 months. Median PFS and OS were 3.5 and 14.5 months, respectively. The most common grade 3/4 adverse events were thrombocytopenia (32%), mucositis (22%), neutropenia (22%), and anemia (18%).

 

Romidepsine (HDAC inhibitor):  niet beschikbaar in NL

Falchi et al. Blood 2021

Patients: 25 treatment naïve or who had R/R PTCL

Methods: azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days.

Results: ORR and CR were 61% and 48%. The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease.

 

Palliatief:

Bortezomib

Lenalidomide

Nieuw: Jak inhibitor 

Allogenic SCT: 

In the setting of R/R PTCL, allogeneic stem cell transplantation remains the only treatment that can significantly lead to long term DFS, as reported in several retrospective analyses. Recently, Loirat et al. reported the results from an intent-to-treat analysis of upfront allo-SCT for PTCL showing promising outcome (5-year OS 72%) when allo-SCT was actually performed.