Allogeneic haematopoietic cell transplantation in peripheral T-cell lymphoma: recommendations from the EBMT Practice Harmonisation and Guidelines Committee

Key points:  See Panel 1 and Figure 1 in the original paper.

●      Hematopoietic cell transplantation (HCT) in first-line treatment:

○      Consider clinical trials whenever possible.

○      In transplant-eligible patients with complete metabolic response, autologous HCT consolidation should be considered.

○      For patients with ALK-positive anaplastic large cell lymphoma, autologous HCT is an option for those with high-risk features who have had a complete metabolic response; however, its role is challenged by brentuximab vedotin (BV) in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) or cyclophosphamide, doxorubicin, etoposide, and prednisolone (CHEP) regimens.

○      There is currently no indication for consolidative allogeneic HCT in patients in first complete response.

○      For patients who are not in complete response, treatment should be regarded a failure, and allogeneic HCT should be considered.

●      Patients with refractory or relapsed peripheral T-cell lymphoma:

○      Allogeneic HCT is the treatment of choice for all eligible patients:

With insufficient response or are refractory to first-line therapy.

With relapsed disease after first complete response, regardless of prior treatment, including autologous HCT.

○      In allogeneic HCT-ineligible patients, autologous HCT might be considered for those who have relapsed disease after achieving a first complete response and have reached another metabolic complete response.

●      Weighing age, performance status, and comorbidities for

allogeneic HCT indication:

o   Candidates with an HCT comorbidity index (HCT-CI) score of 2 or less and a good performance status are most suitable for allogeneic HCT; however, these factors must be considered in conjunction with age, comorbidities, and disease status to determine the overall risks of allogeneic HCT.

●      Salvage regimen selection: 

○      Participation in a clinical trial is encouraged.

○      Platinum-based or gemcitabine-based (eg, dexamethasone, cytarabine, and cisplatin or carboplatin [DHAP]) regimens are preferred.

○      In CD30-positive non-anaplastic large cell lymphoma, BV-based therapies in combination with chemotherapy are an alternative (off-label use).

○      In anaplastic large cell lymphoma, BV, either as monotherapy or in combination, is recommended for patients who have previously responded to BV.

○      In ALK-positive anaplastic large cell lymphoma without previous response to BV, ALK inhibitors such as crizotinib or brigatinib (off-label use) might be considered.

●      Peripheral T-cell lymphoma subtypes:

o   Histology subtype should not be a determining decision-making factor for allogeneic HCT.

●      Donor selection, stem cell source, and graft-versus-host disease (GVHD) prophylaxis: 

○      The preferred donor hierarchy is as follows: matched sibling donor, matched unrelated donor, haploidentical donor, mismatched unrelated donor.

○      Both peripheral blood stem cells and bone marrow are acceptable graft sources.

○      GVHD prophylaxis should be guided by the degree of HLA-matching of recipient and donor, the type of conditioning, and the source of stem cells.

●      Conditioning regimens: 

○      There is no clear superiority of myeloablative conditioning over reduced intensity conditioning or vice versa, making reduced intensity conditioning the preferred choice to broaden accessibility to allogeneic HCT and to take advantage of the potentially lower non-relapse mortality.

●      Post-transplantation interventions:

○      There are no data to support routine post-transplantation interventions for peripheral T-cell lymphomas.

○      Routine monitoring of residual disease is not recommended due to insufficient availability and evidence.

○      No data support the use of prophylactic or pre-emptive donor lymphocyte infusion in peripheral T-cell lymphomas.

○      Timing of immunosuppression tapering post-transplantation must consider individual risks of relapse and GVHD risks.

●      Post-transplantation relapse management: 

○      If possible, reduce or discontinue immunosuppression.

○      Use donor lymphocyte infusion alone or in combination with chemotherapy or targeted therapy, if available.

○      Second allogeneic HCT should be considered.

○      Inclusion of patients in prospective clinical trials should be strongly considered.

Multiple TET2 mutations confer additional survival benefit in both myelodysplastic and myeloproliferative chronic myelomonocytic leukemia subtypes [Letter to the Editor: Retrospective study]

Highlights:

●      Somatic TET2 mutations (TET2^MT) are present in 40–60% of chronic myelomonocytic leukemia (CMML) patients and are associated with improved overall survival (OS) and acute leukemia-free survival (LFS). This is due, in part, to a protective effect of TET2^MT in the context of adverse ASXL1^MT, resulting in a higher response rate to hypomethylating agents (HMA).

●      This study highlights the prognostic value of TET2^MT status and number in both myelodysplastic (MD)-CMML and myeloproliferative (MP)-CMML, and establishes them as independent prognostic markers.

In the primary cohort of 849 CMML patients, 454 (54%) were classified as having MD-CMML, and 394 (46%) as having MP-CMML. The median (range) number of TET2^MT in MD vs. MP-CMML was 1 (0–4) vs. 0 (0–3), respectively (p<0.001). The median variant allele fraction of all TET2^MT cases was 45%, and was marginally lower among MD compared to MP cases (42% vs. 46%, p<0.001). In multivariate analyses of established CMML risk factors, the presence of 1 or ≥2 TET2^MT were both favorably associated with OS (hazard ratios [HR] and 95% confidence intervals [CI] of 0.65 [0.44–0.96] and 0.47 [0.32–0.68], respectively) and LFS (HR 0.68 [0.48–0.99] and 0.49 [0.35–0.71]) in MD-CMML. In MP-CMML, the presence of 1 or ≥2 TET2^MT retained significance for OS (HR 0.70 [0.49–0.99] and 0.48 [0.31–0.74], respectively), whereas only ≥2 TET2^MT was independently associated with LFS (HR 0.65 [0.45–0.96]).

Furthermore, TET2^MT number identified lower-risk patients even within the intermediate-1, intermediate-2, and high-risk groups of the Mayo-Molecular model, and among the intermediate-1 and intermediate-2 risk groups of the CMML-specific prognostic scoring system-Molecular model.

A separate cohort of 265 CMML patients, including 118 (45%) MD and 147 (55%) MP cases, was used for validation of the survival associations. In MP-CMML, the presence of ≥2 TET2^MT was associated with better OS and LFS.

IPSS-M risk and specific sex-associated somatic mutations predict response to ESA therapy in LR-MDS: building a new score [Retrospective study]

Highlights: 

●      A score that includes the molecular international prognostic scoring system (IPSS-M) score, serum erythropoietin (sEPO) levels, and transfusion dependence predicts erythropoiesis-stimulating agent (ESA) response in low-risk myelodysplastic syndrome (LR-MDS) patients.

●      STAG2 mutations are associated with ESA resistance in LR-MDS male patients.

A European cohort of 535 LR-MDS patients was analyzed using targeted next-generation sequencing to calculate IPSS-M scores and explore the relationship between somatic mutations and ESA response. The integration of the IPSS-M score among the two known variables, sEPO and transfusion dependence, refined the capability to predict response (area under the curve [AUC] 0.71 vs. 0.63, p=0.0004). Based on these three variables, a molecular predictive score, which the authors named ESA-PSS-M (specificity 76%, sensitivity 57%), was generated and validated in an external cohort of 223 LR-MDS cases. Despite the impact of the IPSS-M score, no single mutated gene was linked to ESA response. However, when the cases were stratified by sex at birth, the authors observed that mutations in the X-linked STAG2 gene were significantly associated with ESA resistance in LR-MDS males (OR 0.13, p=0.003).

The authors state that this is the first study based on a large multicenter cohort of patients suggesting that the integration of IPSS-M score and sex-specific

mutations can characterize erythropoiesis defects and guide first-line therapeutic choices for anemic LR-MDS (i.e. ESAs vs. Luspatercept).

Venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed or refractory multiple myeloma (BELLINI): final overall survival results from a randomised, phase 3 study [Update clinical trial]

Highlights:

●      The phase 3 BELLINI (NCT02755597) primary endpoint was met, showing superior progression-free survival (PFS) with venetoclax versus placebo plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. However, venetoclax showed increased early mortality.

●      In this analysis, the updated overall survival (OS) was unfavourable for the venetoclax group compared with the placebo group in the overall study population. In post-hoc analyses, the greatest survival improvements remained restricted to patients carrying biomarkers of t(11;14) and/or high BCL2 gene expression.

From July 19, 2016, to October 31, 2017, 291 patients were assigned to venetoclax (n=194) or placebo (n=97); 33 patients (28 in the venetoclax group and five in the placebo group) remained on treatment at the time of this analysis.  At 45.6 months (interquartile range 43.6–48.3) median follow-up, median OS was not reached in the venetoclax group (not reached [NR], 95% CI 44.4–not estimable) or in the placebo group (NR, 95% CI 44.0–not estimable; hazard ratio [HR] 1.19, 95% CI 0.80–1.77; p=0.39). Median PFS was 23.4 months (95% CI 16.2–26.4) with venetoclax versus 11.4 months (95% CI 9.5–14.6) with placebo (HR 0.58 [95% CI 0.43–0.78]; p=0.00026).