Single versus tandem autologous stem cell transplantation in newly diagnosed multiple myeloma [observational study]

Highlights:

●      Tandem autologous hematopoietic stem cell transplantation (ASCT) improves overall survival (OS) and event-free survival (EFS) rates, particularly in patients who did not reach complete remission after initial AHSCT and among older patients, but not for those under 40 years. Patients with ISS III and renal impairment showed worse outcomes with tandem ASCT.

Autologous hematopoietic stem cell transplantation (ASCT) is essential for achieving long-lasting remissions, even in the age of quadruplet induction therapy for patients with newly diagnosed multiple myeloma. It has previously been suggested that high-risk patients' outcomes are improved using tandem ASCT, a second ASCT performed within six months of the first transplant. To determine whether ASCT is beneficial for all age groups and whether the higher remission rates before ASCT in recent years translated into more prolonged survival for all age groups, the authors analysed the data from the German Registry for Hematopoietic Stem Cell Transplantation and Cell Therapy (DRST). The study compared a cohort of patients who received tandem ASCT (n=4027) with patients who did not receive a second transplant [single ASCT (n=6,581)] and patients who did receive a second transplant (autologous or allogeneic) but not within the 6 months after the first ASCT [auto-auto SCT with >183 days between 1st and 2nd (n=1,744) and auto-allo SCT in relapse (n=931)]. Before 2008, the median age at first ASCT was 59.13 years; after 2017, it was 61.36 years (p<0.001). Additionally, transplantation procedures changed over time, with tandem ASCT becoming less prevalent in recent years (47.4% before 2008 to 25.7% after 2017, p<0.001). No significant differences were found in patients who achieved complete remission (CR) after the first transplantation compared to other transplant strategies (p=0.66 for OS, p=0.21 for EFS). However, a significant benefit was noted in patients receiving tandem ASCT who did not achieve CR after the initial ASCT (p<0.001 for OS;  proportional hazard assumptions not supported for EFS) or after induction therapy. A significant benefit of tandem transplantation was found for those patients with ISS stage I and no renal impairment concerning OS (p=0.026). On the other hand, patients with ISS III and renal impairment who had a single ASCT had better OS outcomes compared to the tandem transplant cohort (p=0.011). In patients harboring cytogenetic aberrations, the study did not observe significant benefit for a tandem strategy in either OS [p=0.99, p=0.58, p=0.97, and p=0.99 for t(4;14) for t(14;16), del17p, and ampl(1q), respectively] or EFS [p=0.17, p=0.77, p=0.93, and p=0.95 for t(4;14), t(14;16), del17p, and ampl(1q), respectively]. Similarly, there was no significant difference when combining the cytogenetic profile as “at least one high-risk aberration present” vs. “no aberration present”. According to the multivariable analysis, younger age was associated with better OS and EFS outcomes in both single and tandem ASCT regimes. In conclusion, tandem transplantation is an option for younger patients, particularly in those without CR after initial ASCT and no renal impairment.

Utility of the 2024 best practice recommendations from the EBMT Cellular Therapy and Immunobiology Working Party for use of donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation [Correspondence].

Highlights:

The recent EBMT recommendations for administering donor lymphocyte infusion (DLI) applied in the real world, resulting in better outcomes for allogeneic transplant patients and a lower incidence of grade 2–4 acute graft-versus-host disease (aGvHD).

Recently, the Cellular Therapy and Immunobiology Working Party (CTIWP) of the European Bone Marrow Transplantation (EBMT) Society published consensus-based recommendations for the administration of unmanipulated DLI. However, external validation is needed to support their use in clinical practice because this therapy is associated with a higher risk of non-relapse mortality (NRM). This study retrospectively analyzed a cohort of 162 patients receiving DLI after allogeneic hematopoietic stem cell transplantation (allo-HSCT) between 2010 and 2023. The primary outcomes were analyzed considering if the first dose of DLI was administered in accordance or not with the EBMT 2024 recommendations depending on indication (prophylactic, pre-emptive, therapeutic), donor type (matched related donor, MRD; matched unrelated donor, MUD; mismatched unrelated donor, MMRD; or haploidentical donor, Haplo) and time after transplantation (3 months or 6 months or later). Patients receiving DLI according to the EBMT recommendations had improved 3-year overall survival (OS) (81%, 95% confidence interval [CI]: 71–92%) compared to patients receiving different doses (45%, 95% CI: 36–57%; p<0.0001). In the cases of prophylactic and pre-emptive DLI, the majority of patients were treated according to the EBMT 2024 recommendations (prophylactic DLI: 67% and pre-emptive DLI: 59%), but regarding the administration of therapeutic DLI, only 9% of patients received the recommended doses. In a subgroup analysis of patients receiving pre-emptive DLI, doses according to EBMT guidelines showed a significantly improved 3-year OS (87%, 95% CI: 77–98%) compared to patients receiving different doses (58%, 95% CI: 40–84%; p=0.014). The difference was related to a higher cumulative incidence of NRM and grade 2–4 aGvHD) in patients who received preemptive DLI at doses higher than the ones recommended by EBMT. These data support the new EBMT 2024 recommendations on DLI administration in allo-HSCT.

Expedited evaluation of hereditary hematopoietic malignancies in the setting of stem cell transplantation [Letter to the editor].

Highlight(s): 

Hereditary hematopoietic malignancy (HHM) testing through DNA sequencing of donor’s saliva, peripheral blood or DNA previously provided for human leukocyte antigen (HLA) testing. This approach can reduce the time for identifying germline variants and potentially mitigate the possible consequences of donor-derived malignancies.

Novel techniques for HHM evaluation in the transplant setting have revolutionized the field of risk reduction in hematology. Germline variants associated with HHM are related to several complications, particularly graft failure and donor-derived malignancies. For this reason, clinical HHM testing can mitigate the possible consequences of donor-derived malignancies. However, the method of sequencing DNA from cultured skin fibroblasts is cumbersome. In this observational study, the primary outcome was to evaluate the utility of a risk mitigation strategy through expedited HHM testing (via DNA sequencing from donor HLA samples, saliva, or blood) vs. the "classical" approach using cultured skin fibroblasts. Data from transplant recipients who underwent HHM evaluation were divided into four groups: group 1 had transplant recipients with incidental germline variants detected via tumor-only genomic profiling (n=3) without personal or family antecedents that raised concerns of an HHM; group 2 had patients (n=5) with personal and family history of HHM but with negative HHM testing; group 3 comprised two patients with HHM early in their clinical course who had not yet proceeded to transplant, but were undergoing HHM-focused donor evaluation ("ideal" timelines for HHM evaluation); group 4 had patients (n=12) with personal or family histories that raised concerns about an HHM without complete HHM testing before the transplantation but with donor-focused HHM evaluation. In group 1, the incidental HHM-germline variants detected via tumor-only genomic profiling disappeared after induction therapy (CEBPA, RECQL4, and TERT were the somatic variants identified). In group 2 with negative HHM evaluation (DNA from cultured skin fibroblasts), the investigators used matched-unrelated donor (MUD) transplants because of a strong suspicion of an undiagnosed HHM; one patient carried a germline PALB2 pathogenic variant which was discordant with the patient’s phenotype and the patient received a MUD transplant with good response 97 days after transplantation. For group 4, expedited HHM testing was pursued via DNA sequencing from donor HLA samples (n=5), saliva (n=1), or blood (n=4). Two patients did not have an MRD without the HHM-related variant in question.

This donor-focused HHM screening approach reduced the median turnaround time for HHM evaluations (from 64 days with cultured skin fibroblasts vs. 14 days with the donor-focused approach (p<0.05). In the authors' opinion, this method of expediting HHM evaluations is helpful in urgent transplant situations that prohibit the "classical" approach of sequencing DNA from cultured skin fibroblasts. After a median follow-up of >1 year, all patients in this study have been free of graft failure, HHM-related transplant morbidity, and donor-derived malignancies.

Incidence, risk factors, and outcomes of BK hemorrhagic cystitis in hematopoietic stem cell transplantation from HLA-matched and haploidentical donors with post-transplant cyclophosphamide [Retrospective study].

Highlights:

●      Severe BK hemorrhagic cyctisis (BK-HC) was more common in younger recipients and haploidentical transplants and did not impact transplant outcomes and renal function.

The incidence of human polyomavirus BK-HC in adult hematopoietic stem cell transplantation (HSCT) recipients ranges from 7% to 54%. Those receiving post-transplant cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD) have a significantly higher incidence of BK-HC. In this retrospective cohort, patients with hematologic malignancies and BK-HC were analyzed for risk factors for BK-HC and its impact on renal function and transplant outcomes. The main objective was cumulative incidence of BK-HC after 72 hours from the last dose of PTCy, and secondary endpoints were glomerular filtration rate over time, non-relapse mortality (NRM), overall survival (OS), and GVHD-free, relapse-free survival (GRFS). Patients received PTCy as GVHD prophylaxis and underwent HSCT at a single center in Spain, from a matched-sibling donor (MSD, n=167), matched-unrelated donor (MUD, n=129), or haploidentical donor (HAPLO, n=103). The median recipient age at transplantation was 54 years (range, 18-71). Patients aged ≤ 55 years with acute leukemias and myeloid malignancies underwent myeloablative conditioning, whereas patients  ≥50 years and with a Hematopoietic Cell Transplantation-Specific Comorbidity Index ≥3, aged >55, or mature lymphoid malignancies underwent reduced intensity conditioning. All patients received mesna (50 mg/kg day +3 and +4). Included were 399 patients with comparable characteristics with or without BK-HC. Ninety patients (23%) experienced grade 2-4 BK-HC with a median time of onset of 29 days post HSCT, and the majority (98%) resolved spontaneously with supportive care alone. Younger age and HAPLO donors were significant risk factors for developing higher-grade BK-HC. BK-HC did not affect OS, NRM, GRFS, or creatinine clearance.

UK consensus statement on the use of plerixafor in healthy stem cell donors  [Letter to the editor].

Highlights:

●      A review of the published evidence confirms the safety and efficacy of plerixafor in allogeneic stem cell donors.

The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have approved plerixafor in conjunction with granulocyte colony-stimulating factor (G-CSF), for the management of CD34+ cell mobilization failures for autologous cell transplantation in patients with lymphoma and myeloma. It is often used worldwide for this indication and has been shown to significantly increase the efficacy of remobilization with a success rate of over 60%. A suboptimal cell dose (<2×10⁶/kg recipient body weight) is attained by 1%–2% of healthy peripheral blood stem cell donations for allogeneic hematopoietic stem cell transplantation (allo-HSCT),  while 7%–10% do not meet the requested cell dose. The use of plerixafor in allogeneic stem cell donors has been the subject of several prospective studies; nonetheless, there is currently no pragmatic guidance  or consensus on this topic. For this reason, this review discusses the impact of plerixafor mobilization on graft composition and the safety and efficacy of plerixafor in healthy donors. The findings show that using plerixafor in addition to G-CSF improves stem cell production in adult allogeneic donors who have poor mobilization, with notable differences in the composition of the cellular graft. Furthermore, plerixafor can be utilized to achieve cell doses for HSCT that are higher than usual (>5×10⁶/kg). The side-effects of plerixafor were presented in 11 studies and the most common adverse effects were nausea, headache, bone, joint or muscle pain, and diarrhea. These events are most frequent in patients administered a higher dose of plerixafor (240mcg/kg). Some rare adverse effects were thrombocytopenia and cytomegalovirus infection. The main recommendations of this review are:

1. Allogeneic donors predicted to achieve a suboptimal collection following G-CSF mobilization could receive plerixafor at a dose of 240mcg/kg. A suboptimal collection is usually defined as <2×10⁶ /kg recipient weight.

2. Plerixafor could be considered for the mobilization of donors where supranormal cell doses are required.

3. Plerixafor could be considered in pediatric donors (<16 years of age)

4. Plerixafor is recommended for use with concomitant G-CSF administration

Measurable residual disease as predictor of post–day +100 relapses after allografting in adult AML [Retrospective Study]

Highlights:

●      Patients with positive measurable residual disease (MRD^pos) at day +70 to +100 after allogeneic hematopoietic cell transplant (Allo-HCT) for acute myeloid leukemia (AML) had worse relapse-free survival (RFS), overall survival (OS) and non-relapse mortality (NRM).

●      Similarly, MRD^pos patients before Allo-HCT was associated with worse RFS, OS, and increased relapse after transplant. Notably, despite high rates of MRD conversion after transplant, pre-Allo-HCT MRD^pos patients who converted to MRD-negativity (MRD^pos/MRD^neg) had worse outcomes (3-year relapse risk of 40% vs.15% [P<.001], 3-year RFS 50% vs. 72% [P<.001], and 3-year OS 56% vs. 76% [P<.001]) when compared to pre-AlloHCT MRD^neg (MRD^neg/MRD^neg).

Pre-transplant MRD assessment by multiparameter flow cytometry has consistently been shown to be an important prognostic factor for patients undergoing Allo-HCT for AML, with MRD^pos patients having an increased risk of early (<3 months) relapse. However, the impact of pre- and early-post-MRD status on late relapse and outcomes is unclear.

A cohort of 1266 adults undergoing Allo-HCT for AML or transformed myelodysplastic syndrome/AML patients in first or second morphologic complete remission with available data on pre- and early (day +70 to +100) post-Allo-HCT MRD testing. Cases who relapsed or died <3 months after transplant were excluded. 261 (21%) patients had positive MRD before Allo-HCT and was associated with higher risk of relapse (at 3 years: 61%, 95% confidence interval [CI], 55-67 vs. 23%, 95% CI, 21-26), lower RFS (at 3 years: 27%, 95% CI, 22-33 vs. 60%, 95% CI, 57-63), and lower OS (at 3 years: 36%, 95% CI, 30-42 vs. 65%, 95% CI, 62-68). Post-Allo-HCT MRD^pos patients were uncommon (11 out of 935 patients [1%]), with high rates of MRD^pos/MRD^neg conversion (92%), while there was only 1 patient who converted from MRD^neg/MRD^pos. Despite high rates of MRD negative conversion after Allo-HCT, MRD^pos/MRD^neg had inferior outcomes compared to MRD^neg/MRD^neg patients, as mentioned above.

The authors conclude that pre-transplant MRD significantly predicts outcomes after Allo-HCT in AML. Despite high rates of MRD conversion at day +100, those with pre-transplant MRD^pos had inferior outcomes, suggesting that pre-transplant MRD^pos patients should be considered for preemptive therapy after Allo-HCT.

Clearance of Driver Mutations after Transplantation for Myelofibrosis [Retrospective study]. 

Highlights:

●      In patients with myelofibrosis (MF), allogeneic hematopoietic cell transplant (Allo-HCT) cleared pathogenic mutations at day 30 in 42%, 73%, and 54% of patients with JAK2, CALR, and MPL, respectively. Clearance at day 100 increased to 63%, 82%, and 100% for JAK2, CALR, and MPL.

●      Patients with clearance at day 30 had a lower incidence of 1 year cumulative incidence of relapse (6%, 95% confidence interval [CI], 2-10 vs. 21%, 95% CI, 15-27). Similarly, patients with day 30 clearance had improved disease-free survival (DFS, 61% vs. 41%)  and overall survival (OS, 74% vs. 60%) at 6-years compared to those without clearance. Mutation clearance also outperformed traditional donor chimerism and was independently associated with a lower risk of progression (hazard ratio 0.36, 95%CI, 0.21-0.61).

Allo-HCT is the only curative intervention for MF; however, the role of mutation clearance after Allo-HCT has not been established. A cohort of 324 patients with primary or secondary MF who underwent Allo-HCT were included. The primary pathogenic mutations were JAK2 in 73%, CALR in 23%, and MPL in 4%. Using digital polymerase-chain reaction assays in peripheral blood, mutations were detected before Allo-HCT and at 30, 100, and 180 days after transplantation to measure clearance and its effect on relapse and cure. Other high-risk mutations (ASXL1, SRSF2, EZH2, IDH1/2, and TP53) were also assessed. The two primary end points were relapse and DFS. Mutation clearance at day 30 was associated with improved 1 year recurrence, DFS, and OS.

Day 30 clearance was independently associated with the risk of relapse after adjusting for the specific pathogenic (JAK2 vs. CALR vs. MPL) mutation and other non-TP53 mutations. Other variables that were independently associated with worse outcomes were accelerated-phase MF at the time of transplant, a diagnosis of post-essential thrombocythemia secondary MF, and the presence of TP53. Pathogenic mutation clearance at day 30 did not differ by TP53 status (47% vs. 50%).

The authors conclude that pathogenic mutation clearance at day 30 after Allo-HCT in MF influences relapse and survival irrespective of the underlying driver mutation. They cautioned against generalizing these findings to patients with TP53 or MPL, given the limited number of patients with such mutations in this study cohort.

Pre-Transplant MRD Does Not Seem to Impact Survival in NPM1-Mutated AML Undergoing Allogeneic Stem Cell Transplantation [Retrospective Study]

Highlights:

●      In patients with NPM1 mutated acute myeloid leukemia (AML) who underwent allogeneic stem cell transplantation (Allo-HCT), those with positive NPM1 minimal residual disease (MRD) before transplant had similar 3-year overall survival (OS, 68% vs. 78%, hazard ratio [HR] 1.42, p=0.39) and 3-year leukemia-free survival (LFS, 60% vs. 74%, HR 1.5, p=0.28) when compared to pre-transplant NPM1 MRD negative patients.

AML with mutated NPM1 represents a distinct molecular subgroup as classified by the World Health Organization (WHO) classification system. MRD status before Allo-HCT is an important prognostic variable with different impacts across MRD assessment modalities and AML subgroups. In the case of NPM1 mutated AML, real-time quantitative polymerase chain reaction (RT-qPCR) allows a sensitivity of 10^-5. The authors explored the impact of pre-transplant NPM1 MRD status in a cohort of 174 patients treated between 2011 and 2022 in complete remission (CR).

174 patients were included in the analysis including 54% with FLT3-ITD, the most common co-occurring mutation. 122 patients (70%) underwent Allo-HCT in CR, with 94 patients being NPM1 MRD positive, and 28 patients MRD negative. NPM1 status was assessed using RT-qPCR with a sensitivity of 10^-5 in bone marrow at diagnosis, post-induction, and 4 weeks prior to Allo-HCT, and then at day 28, 60, 100 and 180. In patients in CR, there were no differences in 3-year OS and LFS between pre-transplant NPM1 MRD status. In multivariable analysis, OS and LFS was associated with presence of complex karyotype (OS: HR 6, 95% confidence interval [CI] 1.68 – 21.4, p<0.01, LFS: HR 3.93, 95% CI 1.13 – 13.6, p=0.037), while relapsed disease before Allo-HCT was associated with worse OS (HR 2.82, 95% CI 1.27 – 6.25, p=0.011) and use of maintenance with improved LFS (HR 0.42, 95% CI 0.19 – 0.95, p=0.037).

The authors conclude that the presence of NPM1 molecular MRD before Allo-HCT does not appear to affect outcomes in NPM1 mutated AML and is in line with the current recommendation to proceed with Allo-HCT consolidation irrespective of NPM1 status without further consolidation.

aGvHDtrackR and cGvHDtrackR: shiny applications for graft versus host disease management and clinical data collection [Clinical Application]

Highlights:

●      aGvHDtrackR and cGvHDtrackR are open-source applications that allow for longitudinal graft-versus host (GvHD) scoring based on the NIH and MAGIC algorithm and allows for record treatment received by the patient. These applications lead to systematic and uniform variable recording that can minimize input error and enhance data collection efficacy.

GvHD is a common complication following an allogeneic hematopoietic cell transplant, with different staging and severity scoring systems depending on the organs involved and chronicity. Longitudinal recording that includes treatment, dose, and response is crucial. However, it can be time-consuming and prone to errors. Current applications allow scoring of GvHD, but none allow longitudinal recording and/or capture treatment received.  The authors developed two open-source applications for acute (aGvHDtrackR) and chronic (cGvHDtrackR) GvHD that incorporate GvHD grading, treatment received and allow data to be exported in a longitudinal patient-specific database. The GvHDtrackR (containing the acute and chronic applications) is available for download at:  Sync.com at: link and Github at: link 

Safety and efficacy of the ROCK-2-inhibitor Belumosudil in cGvHD treatment - a retrospective, German-Swiss multicenter real-world data analysis [Retrospective Cohort]

Highlights:

●      In a cohort of 33 patients with chronic graft-versus-host disease (cGvHD) with a median of 4 lines of treatment, belumosudil resulted in an overall response rate (ORR) of 42% (95% confidence interval [CI] 25-60%) including organ response in all organs except liver (n=2). The median time to response was 3 months (range, 1-9), and 8/14 patients (57%) had a durable response.

Belumosudil is a first-in-class rho-associated coiled-coil-containing protein kinase 2 (ROCK2) inhibitor currently approved for the treatment of cGvHD after at least two lines of treatment based on two phase II trials (ROCKstar and KD025). However, real-world outcomes with belumosudil in Europe are lacking, with most reports originating from North America.

The authors report the outcomes of 33 patients with cGvHD at five centers in Germany and Switzerland. The study included all consecutive patients aged >18 years with persistent cGvHD who received belumosudil for at least 4 weeks at a dose of 200mg/day, later adjusted according to the recommended dosing. Additional immunosuppression was allowed if started at least 1 month before belumosudil. The organ-specific cGvHD response was performed according to the National Institutes of Health consensus criteria at baseline and after 1, 3, 6, 9, and 12 months of treatment.  The ORR was 42% (95% CI 25-60%), with a median time to response of 3 months (range, 1-9), with 12/14 (86%) patients responding within 6 months. The median duration of response was 6 months (range, 0-9).  Steroid dose reduction was achieved in 14 of 22 patients with a median best reduction of 50% (range, 17-100%), including 8 patients with a decrease of at least 50% of the initial dosage. Twenty patients (61%) remained on treatment at the last follow-up.  infectious (n=7) and non-infectious (n=4). One patient died due to pulmonary infection while on belumosudil. Two additional patients died during the observation period at 80 and 282 days after cessation of belumosudil treatment (1 patient with progressive pulmonary cGvHD and 1 patient with pneumogenic sepsis).

These authors conclude these results are consistent with previous clinical trials, including a favorable safety and efficacy profile in this heavily pretreated population with limited therapeutic options

Hematopoietic cell transplantation soon after first relapse in acute myeloid leukemia [Pros and Cons Editorial].

In this volume, Haematologica presents an editorial that employs a systematic evaluation of the advantages and disadvantages of the utilization of hematopoietic progenitor transplantation soon after first relapse in acute myeloid leukemia (AML).

●      Pros: The authors do not suggest that all patients with AML who experience a first complete remission and subsequent relapse should proceed directly to transplantation. This decision must be made on an individual basis, considering the specific circumstances of each patient. They posit that the prevailing clinical practice of administering pretransplant re-induction therapy to all patients with AML who experience a relapse is not substantiated by robust scientific evidence and is likely to result in more adverse outcomes than beneficial ones.

●      Cons: In the absence of definitive prospective studies, the current practice of treating relapsed patients with chemotherapy prior to transplant remains, with notable exceptions, a reasonable standard based on a sound rationale and supported by a multitude of retrospective studies. See Figure 2 in the original (Cons) article.

A phase 2 multicenter trial of ruxolitinib to treat bronchiolitis obliterans syndrome after allogeneic HCT [Clinical trial].

Highlights: 

●       Bronchiolitis obliterans syndrome (BOS) occurring after allogeneic hematopoietic cell transplantation (HCT) is a high-risk manifestation of chronic graft-versus-host disease.

●       Ruxolitinib therapy was associated with improvements in lung function for participants with BOS.

●      Clinical responses were more commonly observed in participants with mild or moderate BOS, suggesting that identifying and treating disease before it reaches advanced stages is imperative.

In this prospective, multicenter phase 2 trial (NCT03674047), adult participants (n=49) with BOS were treated with ruxolitinib 10 mg twice daily, continuously in 28-day cycles for up to 12 cycles. The primary objective was to evaluate the early treatment effect of ruxolitinib, assessed by the change in FEV1 (forced expiratory volume in 1 second) at 3 months compared with enrollment.

The best lung-specific overall response rate on ruxoltinib for the 49 participants was 34.7% (16.3% complete response and 18.4% partial response) Nine severe infectious events occurred and were largely respiratory in nature. These results support the use of ruxolitinib in the management of BOS after allogeneic HCT.