Safety but limited efficacy of donor lymphocyte infusion for post-transplantation cyclophosphamide-treated patients [Retrospective Cohort].

Highlights:

despite the low rate of graft-versus-host disease, the donor lymphocyte infusion in patients after post-transplantation cyclophosphamide has low efficacy in treating relapse or stabilizing graft function, unless given in the setting of serotherapy-containing pre-HCT conditioning.

One important method for treating and preventing post-transplant recurrence is donor lymphocyte infusion (DLI). Nonetheless, there remains a risk of graft-versus-host disease (GVHD) following DLI. Compared to traditional GVHD prophylaxis, the risk of GVHD induction by DLI appears to be decreased in patients receiving post-transplantation cyclophosphamide (PTCy). A retrospective cohort from the USA evaluated this effect in 21 patients who received at least one DLI after 22 PTCy-based transplants. The indications for the 38 DLIs were mixed chimerism (n = 20), relapse or progression of hematologic malignancy (n = 9), poor immune reconstitution or uncontrolled infection (n = 7), and delayed primary engraftment (n = 2). The efficacy was limited, with a no sustained response of 50% in 12 patients who received DLI for mixed chimerism. Of these patients, 5 experienced secondary graft failure. In relapsed/progressive hematologic malignancy, three patients had no response, 2 had a partial response, and one had a complete response. All patients had a response (1 incomplete and 2 complete) for the indication of infection resulting from poor immune reconstitution. Regarding the toxicity of DLI, 38 DLIs were administered, with only 3 cases of acute GVHD, 3 cases of cytokine release syndrome, and one case of chronic GVHD. Interestingly, two cases of autoimmunity occurred later post-DLI: dermatomyositis/systemic lupus erythematosus overlap syndrome, and vitiligo. In conclusion, the therapeutic efficacy of DLIs is limited, except for the control of infection with an acceptable toxicity profile of GHVD.

Minimally Invasive Assessment of Peripheral Residual Disease During Maintenance or Observation in Transplant-Eligible Patients With Multiple Myeloma [Prospective Cohort]

Highlights:

In patients with multiple myeloma (MM), the assessment of peripheral residual disease (PRD) in blood has prognostic significance during maintenance or surveillance following autologous hematopoietic stem cell transplantation.

A less invasive technique for assessing response in MM clinical trials is PRD. Mass spectrometry (MS) and next-generation flow (NGF) in peripheral blood could be complementary and offer PRD monitoring in patients with MM who are eligible for transplant. A subgroup analysis of GEM2012MENOS65/GEM2014MAIN clinical trials showed the follow-up results of 138 patients with evaluations of PRD by NGF and MS (overall survival [OS] and relapse-free survival). Sixteen patients (11.6%) were PRD positive (by NGS) and had a 13-fold increased risk of progression and/or death; median progression-free survival (PFS) and OS were 2.5 and 47 months, respectively. In a multivariate analysis of PFS including the Revised International Staging System (R-ISS) at diagnosis and the complete remission status, only measurable residual disease (MRD) in bone marrow, and PRD by NGF showed independent prognostic value for PFS. Paired detection of PRD by NGS identified three subgroups with different survival outcomes, but in the NGF-/MS+ subgroup, positive MS was associated with inferior PFS (54%, 95% CI, 36.8 to 80), although not OS (100%). PRD by NGF showed positive and negative predictive values of 100% and 73%, respectively, compared with MRD as the reference. In transplant-eligible patients with MM, periodic monitoring of PRD may be useful in the dynamic monitoring of residual disease, similar to MRD in bone marrow. Double positive PRD by NGS/MS was associated with low PFS and OS. However, discordant results of PRD (NGS-/MS+) and PRD-/MRD+ were associated with more heterogeneous clinical outcomes.

Allogeneic blood or marrow transplantation using haploidentical grandchildren donors and post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis [Retrospective Cohort]

Highlights:

older allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients with grandchild donors had comparable overall survival and relapse-free survival rates to those with child donors.

Considerable interest exists in identifying eligible donors for allo-HSCT (blood or marrow)in older patients. Allografts from haploidentical relatives can be used safely and effectively when administering high-dose post-transplant cyclophosphamide. However, the survival outcomes for recipients may be limited since older patients have older siblings and children. A recent retrospective cohort from Johns Hopkins Hospital evaluated the outcomes of patients whose donor was one of their children (C group) and those whose donor was one of their grandchildren (GC group). The Kaplan- Meier method estimated overall survival (OS) and relapse-free survival (RFS). Forty patients with grandchildren donors were compared with 276 patients aged 55 years or older who received allogeneic transplants from children donors. The 2-year OS was similar between the two groups (60% in the C group vs. 62% in the GC group; hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.53–1.75, p=0.90) as well as the 2-year relapse-free-survival (55% in the C group vs. 50% in the GC group; HR 1.05, 95% CI 0.62–1.77, p=0.85). After propensity score matching, the 2-year OS and RFS remained similar between the two groups, although the percentage of patients above the age of 70 years remained higher in the GC group (69%) compared with the C group (55%). These data are favorable with the clinical practice of expanding the pool of donors to include haploidentical grandchildren when considering allo-HSCT in older patients.

Venetoclax-based salvage therapy as a bridge to transplant is feasible and effective in patients with relapsed/refractory AML (Retrospective Cohort)

Highlights:

Bcl-2 inhibition with venetoclax (VEN) is a feasible and effective bridging strategy to allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with refractory or relapsed (R/R) acute myeloid leukemia (AML).

Azacytidine and VEN (a B-cell lymphoma 2 inhibitor) treatment has been established as the new standard of care for first-line treatment for older or unfit AML patients. However, comparative studies with azacytidine and VEN for medically fit patients with R/R AML as a bridge-to-transplant strategy are limited. Currently, non-intensive and intensive salvage therapy strategies are available for patients with primary R/R AML, and a VEN-containing salvage therapy may also be helpful for this population with an adverse prognosis. A retrospective cohort in Germany compared the overall survival (OS) and relapse-free-survival in 37 patients (of whom 26 patients had been refractory to intensive induction chemotherapy and 11 patients who had been diagnosed with morphologic or molecular relapse) and 90 patients from the German Study Alliance Leukemia AML registry, who were treated with non-VEN containing salvage therapy according to their treating physician’s choice (TPC). The overall rate response (ORR) was 62% in the VEN cohort compared with 42% in the TPC cohort (p=0.049). 39 (46%) of patients from the TPC cohort and 8 (22%) from the VEN cohort failed to achieve a bone marrow blast clearance after the salvage therapy (p=0.015). Overall, 27 patients (73%) in the VEN arm and 57 patients (63%) from the TPC cohort subsequently underwent allo-HSCT (p=0.41). In conclusion, these results suggest that VEN-containing salvage strategies may be feasible and effective in R/R AML as a bridge to allo-HSCT.

Salvage autologous transplant in relapsed multiple myeloma: long-term follow-up of the phase 3 GMMG ReLApsE trial [Randomized Controlled Trial]

Highlights:

●      In patients with relapsed refractory multiple myeloma (RRMM) treated after 1-3 previous lines of treatment not refractory to lenalidomide (LEN), treatment with LEN and dexamethasone (DEX) until progression of disease showed no differences in terms of progression free survival (PFS) and overall survival (OS) when compared to LEN/DEX followed by salvage melphalan 200mg/m² autologous stem cell transplant (ASCT) and LEN maintenance.

The role and efficacy of salvage ASCT in the era of novel treatments for RRMM is poorly defined, but current guidelines recommend it for patients with time to first progression after frontline salvage high-dose chemotherapy (sHDCT)/ASCT (TTP1) of at least 18 months or 38 months when maintenance is used following upfront ASCT. The ReLApsE trial was a multicenter, phase 3 randomized controlled trial conducted in Germany that evaluated patients with RRMM after 1-3 lines that were not refractory to LEN, aged ≤75 years, with TTP1 of at least 12 months. 282 patients were randomized to continuous LEN/DEX until progression (control arm) or LEN/DEX re-induction followed by melphalan 200mg/m2 salvage ASCT and LEN maintenance (transplant arm).Treatment continued for both arms until there was progressive disease or toxicity.

The primary and secondary endpoints were PFS and OS, respectively. 93% and 94% of patients received upfront sHDCT/ASCT in the ASCT and LEN/DEX group, respectively, and only 9 and 13% of patients, respectively, had prior exposure to LEN.

After a median follow up of 99 months, there were no differences in median PFS (20.5 vs. 19.3 months, hazard ratio [HR] 0.98, 95% confidence interval [95% CI] 0.76-1.27; P= 0.9) or OS (67.1 vs. 62.7 months, HR 0.89, 95% CI 0.66-1.2, P =0.44) between the transplant and LEN/DEX arm, respectively. There were no benefits across different subgroups (upfront ASCT, single vs tandem ASCT, age, baseline renal function, International Staging System [ISS]/ revised-ISS, cytogenetic risk, baseline lactate dehydrogenase, prior lines of treatment, or maintenance treatment after initial ASCT). TTP1 was associated with improved PFS and OS in the overall trial population, but there were no differences in PFS or OS across the two study arms with respect to any specific TTP1 cut-off.

The authors conclude that the results of this trial do not support the use of sHDCT/ASCT in RRMM after previous frontline HDCT/ASCT regardless of TTP1. Importantly, TTP1 or any other biomarker/subgroup was associated with improved outcomes with ASCT compared to LEN/DEX. The authors highlight the small number of patients without previous ASCT and acknowledge that salvage ASCT may still be appropriate in selected cases.

Extramedullary disease but not paraskeletal disease portends inferior outcomes after CAR T cell therapy in multiple myeloma [Retrospective Study] 

Highlights:

●      Patients with multiple myeloma (MM) with extramedullary disease (EMD), defined as plasmacytoma without contact with any osseous structure were associated with inferior reduced progression-free survival (PFS) and overall survival (OS) when compared to patients without EMD after treatment with BCMA chimeric antigen receptor (CAR) T-cell therapy.

●      Conversely, patients with paraskeletal disease (PSD), defined as plasmacytomas contiguous to bone, had no differences in PFS or OS when compared to  MM patients without EMD or PSD treated with BCMA directed CAR T-cells.

EMD has been associated with inferior outcomes in MM across different treatment modalities. However, significant heterogeneity in the terms and definitions of EMD exists, with PSD and EMD often grouped together.

The authors report the outcomes of 134 relapsed/refractory MM patients treated with BCMA CAR T-cell therapy between 2017 and April 2023. The cohort included 25 patients with PSD-only, 34 patients with EMD, and 75 patients with bone marrow (BM)-only disease. 59 patients received ciltacabtagene autoleucel and 52 patients received idecabtagene autoleucel.

After a median of 30.2 months, patients with EMD had shorter median PFS when compared to BM and PSD-only patients (9 vs. 24.2 vs. 21.4 months,  hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.31-3.54, P=0.005, respectively). The median OS was not reached for patients with BM or PSD-only, whereas for patients with EMD it was 24 months (HR 3.7, 95% CI 1.81-7.94, P=0.0005). EMD patients with a high tumor burden had a lower overall response rate (ORR), with patients with EMD tumor burden <25 cm², 25–50 cm², and >50 cm² having an ORR of 81.0% (66.7% complete response, CR), 83.3% (50% CR), and 57.1% (0% CR), respectively.

The authors conclude that EMD, but not PSD, is strongly associated with inferior outcomes following BCMA CAR T-cell therapy, and highlight the importance of a clear definition of EMD.

Posttransplant cyclophosphamide as GVHD prophylaxis in patients receiving mismatched unrelated HCT: the PHYLOS trial [Prospective Phase II Trial]

Highlights:

●      In patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing 7/8 human leukocyte antigen (HLA) mismatched hematopoietic cell transplant (HCT) with myeloablative regimens, a graft-vs-host disease (GvHD) prophylaxis regimen of post-transplant cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil resulted in a 100-day cumulate rate of acute GvHD grade 2-4 of 18.2%, grade 3-4 6.5%, 1-year chronic GvHD incidence 13.4, and a 1-year cumulative non-relapse mortality (NRM) of 9.1%.

Single HLA-A, B, C, or DRB1 mismatch (7/8) HCT is associated with increased risk of severe acute GvHD, increased NRM, and decreased overall survival (OS) when compared to matched HCT. PTCy has been shown to improve outcomes after haploidentical and mismatched HCT, however high rates of GvHD when used alone in matched HCT suggest additional immunosuppression is required.

The authors present the results of a phase II multicenter, single-arm trial. Patients with AML/MDS in complete remission and Eastern Cooperative Oncology Group (ECOG) performance status <2 were planned to receive 7/8 mismatched unrelated HCT with a myeloablative regimen (busulfan, fludarabine). GvHD prophylaxis consisted of PTCy at a dose of 50mg/m² on days +3 and +4, a calcineurin inhibitor (tacrolimus or cyclosporine), and mycophenolate mofetil. A total of 77 patients (of 81 screened) were included in the final analysis (64 AML, 13 MDS), treated between January 2020 and November 2022. The primary endpoint, 100-day cumulative incidence of grade 2-4 acute GvHD, was 18.2% (14 patients, 95% confidence interval [CI], 10.6-27.6). All 14 patients had gut involvement, and 9 of these had 2 or more organs involved. Seventy-one (92%) patients achieved engraftment and complete chimerism by day +30, with a median time to neutrophil and platelet engraftment of 17 and 22 days, respectively. The 1-year cumulative incidence of any grade chronic GvHD (10 patients) was 13.4% (95% CI, 6.9-22.1), with 7 of the 10 patients experiencing moderate/ severe cGvHD. The 1-year NRM, OS, and GvHD-free, relapse-free survival rates were 9.1%, 55.3%, and 78.6%, respectively.

With limitations such as the absence of a control group, a relatively short (1 year) follow-up, and the possible impact of different HLA loci mismatches, the authors conclude these results are comparable to other cohorts previously presented and support the use of this GvHD prophylaxis regimen for 7/8 mismatched unrelated donor HCT.

Utility of Thrombopoietin Receptor Agonists for Prolonged Thrombocytopenia After Chimeric Antigen Receptor T-cell Therapy [Retrospective Study]

Highlights: 

●      In patients treated with chimeric antigen receptor (CAR) T-cell therapy experiencing prolonged (>14 days) thrombocytopenia, the use of a thrombopoietin receptor agonist (TPO-RA) resulted in similar rates of thrombocytopenia improvement (73% vs. 75%, P=1.0) and median time to thrombocytopenia resolution (56 vs. 41 days, P=0.14) compared to patients not treated with TPO-RA.

Chimeric Antigen Receptor (CAR) T-cell therapy is associated with high rates of response but is often associated with prolonged cytopenia, with incidence varying by product, disease setting, and patient characteristics. TPO-RA is used for CAR T-cell therapy-related prolonged thrombocytopenia, but there is a lack of clinical data on its efficacy.

The authors present the outcomes of 85 patients with prolonged (>14 days) thrombocytopenia following CAR T-cell therapy at a single institution. Out of 85 patients, 12 (14%) received TPO-RA (11 patients eltrombopag), whereas the remaining 73 received no TPO-RA (supportive care group). Platelet recovery was similar between the two groups. There were no significant differences in baseline characteristics between the two groups, and baseline platelets before CAR-T therapy and thrombocytopenia severity were similar between groups, with 70/83 patients exhibiting severe (<20 x 10³ cells/mL) thrombocytopenia. In the supportive care group, 53 patients (73%) experienced resolution of thrombocytopenia, compared to 9 patients (75%) in the TPO-RA treated group (P= 1.0), and as described above, there were no differences in time to thrombocytopenia improvement.

Acknowledging the limitations of the study due to size and retrospective nature, the authors conclude their findings do not support the use of TPO-RA for prolonged thrombocytopenia following CAR T-cell therapy.

How I approach hematopoietic stem cell transplantation for CML in a TKI world [Review] 

Key points: 

see Table 1 and Figure 1 in the original article.

●       Allogeneic hematopoietic stem cell transplantation (HSCT) remains an important tool in the treatment of tyrosine kinase inhibitor (TKI) resistant/intolerant chronic or accelerated phase chronic myeloid leukemia (CML), on treatment accelerated phase CML and blast phase CML.

○      Chronic phase:

■      Failure to 3 lines of TKI, including third TKI (ponatinib).

■      T315I mutation +/- resistance or intolerance to ponatinib.

■      New additional chromosomal abnormalities in particular major route cytogenetic abnormalities.

■      TKI intolerance + persistence of grade 4 cytopenia despite dose reduction/interruption.

■      TKI intolerance + bone marrow aplasia (urgent).

■      Severe adverse effects other than cytopenia inducing intolerance on all the TKIs available tested despite dose reduction/interruption.

○      Accelerate phase:

■      TKI naïve without T315I mutation or MECOM and progressing under TKI therapy.

■      TKI  naïve and no optimal response after TKI has been given.

■      TKI  naïve  with T315I mutation or MECOM. 

■      TKI resistant/intolerant.

○      Blastic phase:

■      TKI  naïve  or pretreated with TKI (urgent).

●      Post-allogeneic HSCT relapses can be cured with combined pharmacological and immunological interventions.

Diagnostic accuracy of liver stiffness measurement for the diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome after hematopoietic stem cell transplantation (HSCT), the ELASTOVOD STUDY: an investigator-initiated, prospective, multicentre diagnostic clinical trial

Highlights: 

●      Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a severe complication following allogeneic HSCT (allo-HSCT), traditionally diagnosed based on clinical criteria.

●      This study aimed to evaluate the diagnostic performance of liver stiffness measurement (LSM) as a non-invasive tool for non-invasive diagnosis of VOD/SOS.

●       LSM is a reliable, non-invasive diagnostic tool for VOD/SOS.

The study enrolled 774 adults and 167 children across 25 centers. The +100-day incidence of VOD/SOS HSCT was 5.53 and 5.26 in the overall and allo-HSCT population, higher in children (14.3%) than in adults (3.68%). The 100-day overall survival (OS) probability was 89.5% (overall) and 89.0% (allo-HSCT) while one-year OS was 79% and 78%, respectively, with outcomes varying by VOD/SOS occurrence and severity. LSM significantly differed between VOD/SOS patients and non-affected individuals at all post-allo-HSCT time points, correlating with disease severity. A diagnostic algorithm was proposed, achieving ≥95% sensitivity and specificity, with a 6 kPa rule-out and 25 kPa rule-in cut-off, enhanced by the “three-time pre-HSCT rule.” Survivors showed declining LSM over time, while non-survivors did not. Fully recovered patients had lower LSM than non-improvers.