Hematopoietic cell transplantation for older acute myeloid leukemia patients in first complete remission: results of a randomized phase III study [clinical trial]

Highlight(s): 

Although the leukemia-free survival (LFS) was better with consolidation with allogeneic hematopoietic cell transplantation (HCT) than with non-HCT in elderly patients with acute myeloid leukemia (AML) with complete remission, this benefit did not translate into better overall survival (OS).

Retrospective analyses and prospective studies in elderly patients have confirmed the potential of HCT to induce durable long-term remissions. A recent international, prospective, open, randomized, controlled trial compared allogeneic HCT (allo-HCT) versus conventional consolidation therapy in elderly patients (60-75 years of age) with AML after the achievement of first complete remission (CR1). Conventional consolidation was administered according to local protocols. The primary endpoint was restricted mean LFS (RM-LFS) up to 5 years, defined as the time from randomization to the first of the following three events: hematological relapse, initiation of additional anti-leukemic therapy, or death from any cause.  125 patients were randomized to allo-HCT (n=83) or non-HCT (n=42), and 54 were assigned to observation. In total, 66 of the 83 patients in the HCT arm finally received allo-HCT and in the non-HCT arm 35 of the 42 patients received non-HCT therapy. Five-year LFS rates were 28.8% (95%, confidence interval [CI]: 20.4-40.6) in the allo-HCT and 8.9% (95% CI: 3.1-25.7) in the non-HCT arm, favoring allo-HCT (p=0.02). The RM-LFS up to 5 years was 24.5 months (95% CI: 18.9-29.8) in the allo-HCT and 15.6 months (95%, CI: 10.4-20.8) in the non-HCT arm (p=0.02). However, the non-relapse mortality (NRM) was exclusively observed in the allo-HCT arm with a 5-year cumulative incidence of 33.4% (95% CI: 23.0-43.9; Fisher’s exact p<0.0001). Also, the OS was not statistically significant, with five-year OS rates of 31.3% (95% CI: 22.6-43.2) in the allo-HCT arm vs. 27.1% (95% CI: 15.9-46.4) in the conventional consolidation arm (p=0.16). In older and medically less fit patients with AML in CR1, the good anti-leukemic potential of allo-HCT does not compensate for the high NRM in this population, nor is it reflected in a better OS.

Role of Allogeneic Hematopoietic Stem Cell Transplantation for Philadelphia Chromosome-Positive B-Cell Acute Lymphoblastic Leukemia in the Contemporary Era [Review]

Highlights:

In Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia, cure is the goal, and at present, hematopoietic stem cell transplantation (HSCT) is the only treatment with curative potential.

Allogeneic HSCT (allo-HSCT) has always been an integral part of the treatment algorithm of Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ ALL). With potent tyrosine kinase inhibitors (TKIs) and novel targeted therapy, the treatment guidelines for Ph+ ALL are evolving rapidly. The current standard of care for patients with Ph+ ALL is a BCR::ABL1 TKI combined with chemotherapy. Newer combinations of TKIs (dasatinib and ponatinib) and blinatumomab (CD3-CD19 bispecific antibody) as upfront therapy have shown promising results, potentially moving towards low-intensity or chemotherapy-free regimens (SWOG study). Allo-HSCT improves rates of relapse-free survival (RFS) compared to chemotherapy alone (UKALLXII/ECOG 2993 trial) but with higher rates of transplant-related mortality and graft-versus-host disease; also, the combination of dasatinib plus hyper CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose methotrexate and cytarabine), followed by allo-HSCT was associated with superior RFS (p=0.038) and overall survival OS (p=0.037) in a phase II trial. However, other studies did not show a difference in survival between patients proceeding to transplant and those not. Recently, allo-HSCT after upfront immunotherapy plus TKIs has shown that transplant does not improve RFS or OS (D-ALBA trial: dasatinib plus blinatumomab). Possibly, reverse transcription polymerase chain reaction for BCR::ABL1 did not add to the prognostic information for patients who achieved high sensitivity next-generation sequencing-based measurable residual disease (MRD) negativity and in the era of TKIs, the quantitative monitoring of MRD kinetics during therapy aid in identification of subgroups at the highest risk of relapse after transplant. In the same way, patients that achieve complete molecular response (CMR; BCR::ABL1 ≤ 0.01%) at 3 months have excellent long-term outcomes and may be able to avoid allo-HSCT in their first remission. Recent improvements in the platform of haploidentical-HSCT (haplo-HSCT) have demonstrated no difference in OS between haplo-HSCT and fully matched-related or -unrelated donors. The administration of post-transplant maintenance with a TKI was associated with an OS benefit. Treatment options for relapsed and refractory disease include blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor T-cell therapy. However, allo-HSCT continues to be an essential part of the treatment algorithm, and possibly, all eligible patients with Ph+ ALL in second remission, those who do not achieve a CMR after three months, and patients harboring high-risk biological anomalies should be advised to undergo allo-HSCT.

Trends in allogeneic transplantation for favorable risk acute myeloid leukemia in first remission: a longitudinal study of >15 years from the ALWP of the EBMT [Retrospective study]

Highlight(s):

In patients with favorable risk acute myeloid leukemia (AML), the tendency in the last decade has been to show an increased number of transplants in patients ≥60 years, higher rates of haploidentical donors, and graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy). This resulted in better 3-year GHVD-free, relapse-free survival (GRFS) and reduced rates of chronic GVHD.

Although hematopoietic stem cell transplantation (HSCT) is usually not indicated in favorable risk AML at first complete remission (CR1) as these patients  are generally considered to have a good prognosis, relapse occurs in 35–40%% of cases. Most evidence on the improvement in transplant outcomes for AML comes from patients with intermediate- and adverse-risk factors. For this reason, a retrospective and multicenter analysis of the dataset of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) evaluated the outcomes of HSCT in patients with favorable-risk AML (t (8:21), inv (16), and NPM1^mutFLT3^WT) in CR1, and compared them according to the period of transplant during three time periods: 2005–2009, 2010–2014, and 2015–2021. A total of 1850 patients met the inclusion criteria, comprising 526 with t (8:21), 625 with inv (16), and 699 with NPM1^mutFLT3^WT and normal karyotype. Two hundred and twenty-two were transplanted in 2005–2009, 392 in 2010–2014, and 1236 in 2015–2021. More patients ≥50 years were transplanted in the latest period with 52.7% vs. the two earlier periods, 27.9% and 32.1% (p<0.0001), and numbers for age ≥60 years were 25.4% in the 2015-2021 period vs. 8.1% and 11%, in 2005–2009 and 2010–2014, respectively (p<0.0001). Transplants from haploidentical donors increased from 5.9% in 2005–2009 and 2010–2014 to 14.5% in 2015–2021 (p 0.0001). GVHD prophylaxis with in vivo T-cell depletion or PTCy was more frequent in 2015–2021 compared to the other two periods (p<0.0001). The incidence of total chronic GVHD was reduced for transplants performed ≥2015 compared to those performed in 2005–2009 (hazard ratio [HR] =0.74, 95% interval confidence (CI): 0.56–0.99, p=0.046). Also, GRFS improved for patients transplanted in 2010–2014 vs. those transplanted in 2005–2009 (HR=0.74, 95% CI: 0.56–0.98, p=0.037). In conclusion, the recent improvements in the conditioning regimens, the introduction of reduced intensity conditioning, and GVHD prophylaxis with PTCy resulted in favorable outcomes in terms of better GRFS and lower rates of GVHD without impact on overall survival or non-relapse mortality.

Optimal timing and impact of allogeneic peripheral blood stem cell transplantation in adult T-cell lymphoblastic lymphoma: insights from a large cohort multi-center real-world study in Shanghai [Retrospective study]

Highlight(s):

Among patients with adult T-cell lymphoblastic lymphoma (T-LBL), allogeneic peripheral blood stem cell transplantation (allo-PBSCT) significantly lowered the cumulative incidence of relapse (CIR) compared to autologous PBSCT (auto-PBSCT) and non-stem cell transplantation.

Evidence of high-quality studies is necessary in hematopoietic stem cell transplantation (HSCT) for treating T-LBL. A Chinese retrospective study across sixteen hematological centers in Shanghai assessed the clinical outcomes of a cohort of 153 adult T-LBL patients who received auto-PBSCT or allo-PBSCT. With a median follow-up of 42.5 months (range, 6.2–119.7), 77 of 153 patients (50.3%) died, primarily due to disease progression (76.6%, 59/77). The 2-year overall survival (OS) and progression-free survival (PFS) rates were 56.3% (95%, confidence interval  [CI]: 47.8–64.0%) and 47.6% (95%, CI: 39.2–55.5%), respectively. After induction chemotherapy, 99 patients achieved first complete remission (CR), 11 received auto-PBSCT, 74 received allo-PBSCT, and 14 did not undergo transplantation. The 2-year CIR of 23.1% (95%, CI: 14.6–35.5%) in the allo-PBSCT group was significantly lower than that of 55.6% (95%, CI: 28.1–86.5%) in the auto-PBSCT group (p=0.043) and 58.2% (95%, CI: 30.2–87.9%) in the non-transplant group (p=0.001), without statistically significant differences in OS or PFS (p=0.154 for OS; p = 0.164 for PFS). Among patients undergoing allo-PBSCT in CR, early (within four induction courses) and late CR (after four induction courses) did not impact the prognosis at 2-years. In conclusion, allo-PBSCT was found to reduce relapse risk compared to auto-PBSCT in adult T-LBL, but more data are necessary to establish the benefit in OS and PFS.

Budesonide, Added to PTCy-Based Regimen, for Prevention of Acute GI GVHD After Allogeneic Stem Cell Transplantation [Observational Study] 

Highlight(s):

The addition of budesonide to posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is safe and effective in preventing severe acute gastrointestinal (GI) GVHD.

Despite the use of posttransplant cyclophosphamide (PTCy), one-third of autologous hematopoietic stem cell transplantation (AHSCT) recipients experience severe acute GVHD (aGVHD), with the GI tract as one of the most prevalent organs involved. Oral budesonide has shown a high response rate when treating acute GI GVHD. However, the efficacy and safety of budesonide in combination with a GVHD prophylaxis regimen for preventing GI GVHD has not been studied.

A prospective observational study compared the effectiveness of budesonide added to PTCy, tacrolimus, and mycophenolate mofetil. Eighty patients were compared with a dataset of 646 control patients who received PTCy-based GVHD prophylaxis (CIBMTR Study # GV17-02). Budesonide was administered 3 mg orally three times daily, starting on day +5, and tapered starting from day +90. GI GVHD (primary outcome), aGVHD grade II-IV, grade III-IV, chronic GVHD, overall survival (OS), progression-free survival (PFS), GVHD-free, relapse-free survival (GRFS), relapse, and non-relapse mortality (NRM) were compared using propensity score analyses. In patients who received budesonide, the cumulative incidence of acute GI GVHD at 100 days and 1 year was 5.19% (95%, confidence interval [CI]: 1.68–11.74) and 11.09% (95%, CI: 5.15–19.58), respectively. The 3-month cumulative incidence of aGVHD grade II-IV and grade III-IV in the budesonide and control groups were 3.83% vs. 34.43% (p<0.001) and 1.32% vs. 9.83% (p=0.029), respectively. Chronic GVHD at 1-year was 4.68% vs. 29.79% (p<0.001). Similarly, patients treated with budesonide had significantly better OS, PFS, and GRFS. In conclusion, incorporating oral budesonide into the PTCy-based GVHD prophylaxis reduces the incidence of aGVHD and chronic GVHD without compromising treatment outcomes.

Autologous hematopoietic stem cell transplantation for treatment of multiple sclerosis and neuromyelitis optica spectrum disorder — recommendations from ECTRIMS and the EBMT [Guidelines] 

Highlight(s): 

The immune resetting of autologous hematopoietic stem cell transplantation (AHSCT) in relapsing-remitting multiple sclerosis (MS) and neuromyelitis optica spectrum disorder is a highly effective therapy with acceptable safety in patients with treatment failure.

AHSCT is a treatment option for relapsing forms of MS and neuromyelitis optica spectrum disorder that are refractory to disease-modifying therapy. Because there is no published guidance regarding AHSCT for these patients, consensus clinical practice recommendations were developed by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP). Some main recommendations were:

AHSCT in multiple sclerosis (MS):

●      Consider AHSCT as an appropriate escalation therapy for people with highly active MS and in whom high-efficacy disease-modifying therapy (DMT) has failed. This indication should be adopted widely and with equitable access in all geographical areas.

●       Refer patients with highly active, treatment-refractory MS as early as possible for consideration of AHSCT.

●       For people with markers of aggressive disease (frequent relapses, incomplete recovery from relapses, high frequency of new MRI lesions, and rapid onset of disability), AHSCT can be considered within a specialized multidisciplinary assessment pathway after failure of a single high-efficacy DMT after a meaningful period of treatment.  

●       AHSCT as first-line therapy should only be considered for individuals with rapidly evolving, severe MS with a poor prognosis; in this scenario, AHSCT should be offered as part of a clinical trial or an observational, longitudinal research study (if a trial is not available) without delay whenever possible..

●       AHSCT can be considered for young (<45 years) individuals with early progressive MS with a short disease duration and who have well-documented clinical and radiological evidence of inflammatory disease.

●       Offering AHSCT for progressive MS without detectable inflammatory lesion activity is not supported owing to a lack of evidence.

●       Owing to a high risk and low or no benefit, AHSCT is not recommended for the treatment of individuals with long-standing, advanced forms of MS with severe disability.

●       Trials to compare AHSCT with DMTs approved for treating progressive forms of MS are encouraged.

AHSCT in neuromyelitis optica spectrum disorder (NMOSD):

●       Evidence is insufficient to indicate the use of HSCT in NMOSD outside clinical trials, mostly owing to the availability of highly effective treatments.

●       AHSCT could be considered as a rescue therapy for NMOSD that does not respond to treatment, or as an induction therapy for aggressive disease, especially with the use of conditioning regimens that include anti-CD20 or antibody-depleting strategies. .

●       Allogeneic HSCT should only be considered for individuals in whom AHSCT has failed and no other treatment options are available.

AHSCT treatment methodology:

●      To treat MS, intermediate-intensity conditioning protocols, such as carmustine (BCNU), etoposide, cytosine arabinoside (Ara-C) and melphalan (BEAM) with anti-thymocyte globulin (ATG; BEAM–ATG) or cyclophosphamide–ATG, are recommended to achieve the best balance of efficacy and risk in most settings, according to EBMT guidelines.

●       Use of low-intensity regimens (for example, low-dose cyclophosphamide without serotherapy) is not recommended outside clinical trials owing to poor evidence of efficacy.

●       Use of high-intensity, myeloablative conditioning protocols (for example, busulfan–cyclophosphamide–ATG) is not recommended outside clinical trials due to a higher toxicity risk but can be considered at a centre with the specific expertise..

●       For the treatment of NMOSD, when indicated, cyclophosphamide-based conditioning protocols, possibly associated with rituximab, are appropriate: the role of allogeneic HSCT is confined to a rescue treatment option for when NMOSD does not respond to approved biological therapy and relapses after AHSCT

Prophylaxis and care of complications:

●       Offer revaccination after AHSCT according to local, national, and international (ECIL7) recommendations.

●       Monitor for cytomegalovirus and Epstein-Barr virus reactivation with standardized PCR assays, at least over the highest risk period (days 15–60), with a weekly schedule in the first 2 months, and then fortnightly until day 100.

●       Watch and treat or refer promptly for secondary autoimmune disease; these mainly present as thyroiditis or immune thrombocytopenia, but be aware of less common diseases: autoimmune hemolytic anemia, acquired hemophilia, antiphospholipid syndrome, and myasthenia gravis.

Factors associated with survival following allogeneic transplantation for myeloid neoplasms harboring TP53 mutations [Retrospective Study]

Highlights:

●      In a cohort of 134 with TP53 mutated (TP53^mut) myeloid neoplasm (MN), , pre-allogeneic hematopoietic stem cell transplant (Allo-HCT) blast count >5%, co-occurring DNMT3A mutation, and and TP53 mutations outside of the DNA-binding domain (DBD) were associated with inferior relapse-free survival (RFS). Conversely, use of melphalan during conditioning was associated with improved RFS (HR 0.52, p=0.005).

●      Based on the above variables, a hierarchical model was created and stratifies patients into low, intermediate, and high risk categories, with 1-year RFS of 81.3%, 31.3% and 6.7%, respectively (P<0.001).

TP53^mut MN are associated with poor outcomes and although Allo-HCT is the only curative treatment, outcomes are inferior with median survival ~1 year. The authors described the outcomes of 137 patients treated with MN (63 and 71 patients with acute myeloid leukemia and myelodysplastic syndrome [MDS], respectively) at 7 centers in the United States and Australia. Only patients with variant allele frequency (VAF) >2% and for patients with MDS those with multi-hit TP53 loss (defined 93 as 2 TP53^mut 10-49% VAF, or 1 TP53^mut with VAF ≥50%, or 1 TP53^mut VAF 10-49% in the context 94 of 17p loss across TP53 locus) were included.

After a median post-HCT follow-up of 3.68 years (95% CI 3.05–5.52), median overall survival (OS) of the cohort was 1.03 year (95% CI 0.7-1.7). Pre Allo-HCT disease modifying therapy or venetoclax was not associated with differences in overall survival, however, patients with complex cytogenetics (3-year OS rate 13.3% vs. 27.1%, p=0.006) and those with blast pre-Allo-HCT >15% or 5-9% had worse OS when compared to those with <5% (median OS 16 vs. 6 vs. 2 months, p=0.0012). Multivariate analysis showed that harboring non-294 DBD TP53^mut only (HR 3.4, 95% CI 1.4–8.1, p=0.005) and DNMT3A co-mutation (HR 2.64, 295 95% CI 1.2–5.8, p=0.016), and high (>5%) bone marrow blast pre-Allo-HCT (HR 2.7, 95% CI 1.3–5.3, p=0.006) were independently associated with an inferior RFS, while the use of melphalan as part of the conditioning regimen was associated with improved RFS (HR 0.52, 95% CI 0.3-0.8, p=0.005). Using these variable, a hierarchical model was created and stratifies patients into low, intermediate, and high risk categories, with 1-year RFS of 81.3%, 31.3% and 6.7%, respectively (P<0.001).

The authors conclude a subset of patients with TP53^mut derived long-term benefits after Allo-HCT, specially those with low-blast percentage or used melphalan as part of conditioning.

Luspatercept for the treatment of anemia in allo-HSCT for patients with hematological diseases [Letter to the Editor]

Highlights:

●      In a cohort of 16 patients with anemia following allogeneic hematopoietic cell transplant (Allo-HCT) with anemia associated with poor graft function (PGF) or pure red cell aplasia (PRCA), luspatecerpt was associated with improvement in hemoglobin (Hb) in 13 (81.3%) of patients.

●      Luspatercept results in an increase in mean Hb from 5.9 g/dL pre-luspatercept to 8.2 g/dL (p < 0.005), with a median time to response of 7 days (interquartile range, 4-14 days). 30.8% of responders (4 patients) remained transfusion independent at data cut-off

Luspatercept reduces SMAD2 and SMAD3 signaling by binding transforming growth factor-beta superfamily ligans. It has been shown to enhance erythropoiesis and  improve anemia in myelodysplastic syndrome (MDS) with excess ring sideroblast or SF3B1 mutations and beta thalassemia.
The authors report a 16 patient cohort of post Allo-HCT treated with luspatecerpt for anemia. 8 patients received Allo-HCT for myeloid malignancies, 4 for lymphoid malignancies, and 4 for severe aplastic anemia. 13 patients had secondary PGF, 2 patient PRCA, and 1 patient primary PGF. Luspatacerpt was given at a dose of 0.8–1mg/kg in one or two doses at a median time of 134.5 days (39–543) post Allo-HCT. 13 patients (81.3%) were considered to have an erythroid responses, with increase in mean Hb from 5.9 g/dL pre-luspatercept to 8.2 g/dL (p < 0.005). Bone marrow hypoplasia before luspatercept was seen in 6 patients, including 5 responders. There were no differences in mean neutrophil or platelet count before and after luspatercept (neutrophils: 1.7 vs. 2.2 10³/uL, p = 0.26,  platelets 22.5  vs. 37 10⁶/uL, p  = 0.13). The median follow up was 325 days for the cohort. There were two patients with grade 1 toxicity (1 case with fatigue and 1 case with lower extremity edema), and there were no episodes of diarrhea or other grade 2 toxicity. 1 responder died due to adenovirus infection.

The authors conclude this findings provide a basis to explore the use of luspatercept in anemia following post-Allo-HCT.

Low rates of chronic graft-versus-host disease with ruxolitinib maintenance following allogeneic HCT [Clinical Trial]

Highlights: 

●       In this Phase II single-arm study, prolonged administration of ruxolitinib, starting on days +30 to +100 post-allogeneic hematopoietic cell transplant (Allo-HCT) and continued for up to 24 months, was associated with a 1-year graft-versus-host disease (GvHD) free, relapse-free survival (GRFS) of 70%.

●      • Grade III-IV acute GvHD (aGvHD) at 6 months was 4.8%. Moderate-severe chronic GvHD (cGvHD) at 2 years was 16%. The 2-year overall survival (OS) and progression-free survival (PFS) for the cohort were 76% and 68%, respectively.

Ruxolitinib, a JAK1/2 inhibitor, is approved for the management of acute and chronic GvHD following Allo-HCT. Although post-transplant cyclophosphamide (PTCy) and other prophylaxis regimens have improved GvHD rates, this complication is still seen following Allo-HCT. The authors report the results of a multicenter, single-arm, phase II study assessing the use of ruxolitinib in combination with methotrexate and tacrolimus (MTX/Tacro) for GvHD prophylaxis following reduced-intensity conditioning with 7/8 or 8/8 human leukocyte antigen-matched donors, collected from peripheral blood for the treatment of myeloid malignancies. Ruxolitinib was started between day +30-100 (median: day +45) at a dose of 10mg twice a day continuously in 28 day cycles for up to 24 cycles.

78 patients were enrolled, but only 63 patients started ruxolitinib as part of the study. The median follow-up was 41 months (range 10-61). The median number of cycles of with ruxolitinib were 24 (range 2-24), and most patients discontinued (33 patients) due to completion of 24 cycles. GRFS at 1-year, the primary endpoint, was 70% (95% Confidence  Interval (CI) 57-80). The 2-year cumulative incidence of non-relapse mortality was 4.8% (95% CI, 1.2-12); with only one death attributed to GVHD. The 2-year cumulative incidence of disease relapse was 27% (95% CI, 17-38). 8 patients experienced grade ≥3 infections, with most events occurring shortly after ruxolitinib discontinuation for relapsed disease. Recurrent cytopenias (grade ≥3) occurred in 17% of patients, and 35% of patients required dose reduction but only 6 patients discontinued ruxolitinib due to cytopenias.

The author conclude that when compared to previous results in other cohorts,  ruxolitinib in combination with MTX/Tacro yielded comparable GvHD outcomes to those seen with PTCy and improved when compared MTX/Tacro alone and represent an attractive GvHD prophylaxis that will be explored in randomized clinical trials.

Allogeneic Stem Cell Transplantation in Participants With Hematologic Malignancies Following Pembrolizumab Therapy [Retrospective study]

Highlights:

●      In 70 patients who received pembrolizumab within 2-years of allogeneic hematopoietic cell transplant (Allo-HCT) for hematological malignancies, a 6-month cumulative incidence of grade II-IV acute graft-versus host disease (aGvHD) was 41% (95% confidence interval [CI] 30 – 50%) and 1 year-cumulative incidence of chronic graft-versus host disease (cGvHD) was 20% (95%CI,12 - 30%).

Immune checkpoint inhibitors are used across several malignancies, including hematological malignancies such as Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBCL) that may ultimately undergo Allo-HCT.

The authors describe outcomes of 78 patients who participated in 4 clinical trials (KEYNOTE-013, KEYNOTE-087, KEYNOTE-170, and KEYNOTE-204) using pembrolizumab and who underwent Allo-HCT within 2-years of their last pembrolizumab use. 57 patients (81%) had underlying cHL, while other patients had other subtypes of hematological malignancy (PMBCL, multiple myeloma, Richter’s syndrome, amongst others).  The median duration of treatment with pembrolizumab was 5.3 months (range, 0.7 - 29.6), and the median time from last dose of pembrolizumab to allo-SCT was 4.6 months (range, 1 - 20). The 6-month cumulative incidence of aGvHD grade II-IV of 41% (95% confidence interval [CI] 30 – 50%), including grade III/IV of 20% . The 1 year-cumulative incidence of chronic graft-versus host disease (cGvHD) was 20% (95%CI,12 - 30%). The median follow up for the cohort was 40.1, and the median progression-free survival and overall survival were not reached in this cohort.  The estimated 40-month cumulative incidence of transplant-related mortality and relapse rate was 17% (95% CI, 9 - 27%) and 27% (95% CI,16 - 38%), respectively.

The authors conclude the present cohort had similar rates of GvHD to those expected, and given the favorable clinical outcomes (progression-free survival, overall survival and non-relapse mortality) Allo-HCT after pembrolizumab is a safe and feasible option.

Implications of lymphocyte kinetics after chimeric antigen receptor T cell therapy for multiple myeloma [Letter to the Editor]

Highlights:

●      Higher absolute lymphocyte count (ALC), as measured by the complete blood count differential, during the first 2 weeks is associated with improved progression-free survival (OS) and overall survival (OS) following BCMA chimeric receptor antigen (CAR) T-cell therapy for multiple myeloma (MM).

●        Achieving an ALC >1 x 10³/uL was associated with improved progression-free survival (PFS, hazard ratio [HR= 0.65, p = 0.0028)  and overall survival (OS, HR = 0.38, p = 0.017)) in a multivariable analysis after adjusting for ferritin, presence of extramedullary disease or high-risk cytogenetics.

BCMA CAR-T is associated with high-rates of response in relapsed/refractory MM, however, it is not a curative treatment with eventual relapse. Additionally, there is a proportion of patient with early relapse. The absolute lymphocyte count during the first 2 weeks has been associated with CAR-T cell expansion, clinical outcomes, and toxicity.

The authors describe outcomes of 133 patients treated with ciltacabtagene autoleucel (cilta-cel, 73 patients) and idecabtagene autoleucel (ide-cel, 61 patients) for relapsed MM at a single institution. The authors assessed ALC from day 0 through +21 post CAR-T cell infusion and its impact with efficacy and toxicity. The ALC profile was significantly different between CAR-T products, with ide-cel having earlier and lower peak ALC when compared to cilta-cel (0.65 vs. 2.45 x 10³/uL, p < 0.01 , median time to peak 11 vs. 12 days, p = 0.14). With a median follow up of 1.5 years, the median PFS and OS was not reached. Peak ALC and the time to peak ALC was associated with improved outcomes that persisted in multivariable analysis after adjusting for other variables as mentioned above. Importantly, the effect of ALC was seen both when used as a continuous and dichotomous variable. Patients treated with Ide-cel had lower rates of ALC >1 x 10³/uL when compared to cilta-cel (33.9% vs. 79.5%, p < 0.01).

The authors conclude that ALC is an important prognostic factor following BCMA CAR-T and their findings are in line with previous publications.