Pretransplant MRD detection of fusion transcripts is strongly prognostic in KMT2A-rearranged acute myeloid leukemia [Letter to the editor]

Highlights:

KMT2A-rearranged (KMT2Ar) measurable residual disease (MRD) pretransplant in adults with acute myeloid leukemia (AML) was associated with a dismal prognosis with inferior overall survival (OS) and increased incidence of relapse.

Retrospective studies suggest that the patients with AML in remission before hematopoietic stem cell transplant (HSCT) have a higher relapse risk if KMT2Ar molecular MRD is detected. A retrospective study of 64 patients with KMT2Ar AML analyzed the clinical relevance of pre-HSCT KMT2Ar MRD detection using two methods: real-time quantitative polymerase chain reaction (qPCR) and reverse transcription droplet digital PCR (RT-dPCR) assay. Also, the prognostic impact on post-HSCT outcomes was evaluated. Pre-HSCT RNA from bone marrow (n = 59) or peripheral blood (n =5) was assessed by qPCR (n = 55) or RT-dPCR (n = 9). The assays targeted common fusion partner genes, including MLLT3, ELL, AFDN, and AFF1, allowing for the quantification of common KMT2Ar fusion genes. However, MLLT10 and MLLT1 were run separately due to the high degree of breakpoint heterogeneity. Assay sensitivity was ~0.001%. Relapse-free survival (RFS) and OS were assessed using the Kaplan-Meier method, and the cumulative incidence function was used to compute the cumulative incidence of relapse (CIR).

Forty-two percent of patients had KMT2Ar MRD-positive status before HSCT, with a median MRD level of 0.1200% (range, 0.0056%-35.0394%). All patients were in remission at the time of transplant and had received prior intensive chemotherapy. CIR was significantly increased among patients who were KMT2Ar MRD-positive vs. MRD-negative  (2-year CIR: 75% vs. 25%, p= 0.0004). Inferior 2-year outcomes were observed in patients who were MRD-positive vs. MRD-negative pre-HSCT with an RFS of 17% vs. 59% (p=0.001) and 2-year OS of 39% vs. 67% (p=0.012). The hazard ratio of MRD-positive status for inferior RFS was 2.6 (95% confidence interval: 1.3-5.1, p=0.007).  At two years, RFS was 59% and 42% if  KMT2A::X MRD was negative or with a level of 0.001% to <0.1%  but was 0% if KMT2A::X MRD had a level >0.1%.  In conclusion, KMT2Ar at diagnosis is a marker of relapse in patients with KMT2A-rearranged AML. KMT2Ar MRD monitoring at baseline in bone marrow (or peripheral blood) by RT-dPCR or qPCR is a valuable tool for refining prognostication in this population and targeting interventions to reduce the risk of relapse and improve survival outcomes.

How I manage iron overload in the hematopoietic cell transplantation setting [Review]

Highlights: 

Iron toxicity has an impact on the different phases of hematopoietic transplantation, before, during, and after, and for this reason, it is an issue that should be reviewed regularly to avoid permanent organ damage and improve post-transplant survival.

Iron cytotoxicity is related to abnormalities in the dynamic iron balance. In a transplantation setting, hematopoietic stem cell transplantation (HSCT) by itself imposes substantial and prolonged stress on several tissues, and a positive but variable association has emerged between iron overload markers and multiple endpoints related to transplant-related mortality or HSCT complications. Massive erythroid marrow cell death, especially in myeloablative conditioning, results in a significant release of iron (≥ 1 gram). No single time-point measurement of iron overload biomarkers can estimate acquired tissue damage; however, some methods, such as transferrin saturation and serum ferritin, can indirectly estimate the iron load. Moreover, ferritin levels correlate with total body iron stores and clinical outcomes. However, magnetic resonance imaging (MRI) T2*/R2* measurements of cardiac and pancreatic iron deposition are the standard of care for estimating the liver iron concentration (LIC), even though it is not widely available. In the context of transplant, some observational studies have demonstrated that elevated LIC >7 mg/g dry weight and labile plasmatic iron increased the transplant-related mortality at 100 days. For this reason, an iron status workup is necessary to classify the patients into two risk groups: low- and high-risk (the latter group with prolonged transfusion dependence [>20 packed red blod cells units], inconsistent iron chelation treatment, transferrin saturation >50%, serum ferritin >1000 ng/dL, absence of constant control of iron toxicity, transfusion-dependent thalassemia, polytransfused patients with sickle cell disease, long-term aplastic anemia, and prolonged anemia with episodic transfusion needs). The latter group requires closer follow-up with MRI and, in some cases, the consideration of liver biopsy. Hierarchically, when it is time for HSCT, this should not be delayed because of the relevant risk of progression to leukemia and death. The strategic decision to eliminate the malignant clone must take precedence over any iron chelation treatment. An early and constant chelation therapy from the beginning of transfusion dependence is essential for improving HSCT outcomes. The author recommends iron chelation during transplantation in 3 situations:

●       Presence of clearly defined and relevant iron-related clinical issues (mainly heart rhythm disturbances) with clear iron overload. The first choice of treatment is a 24-hour intravenous continuous deferoxamine infusion.

●       Low-dose iron chelation with deferasirox (DFX ) starting at least 4 weeks after transplantation and, ideally, until sustained engraftment is recommended in cases of incomplete/ delayed marrow recovery and high transferrin saturation.

●       After engraftment in the case of persistent hepatocellular toxicity because of documented iron hepatocellular toxicity. The first choice of treatment is oral once-daily administration of DFX.

Iron toxicity is one of several aspects to be evaluated before HSCT. Reducing iron-induced oxidative stress during the transplant phase could further improve outcomes while also recognizing that after transplantation, it is advisable to restore normal iron metabolism.

Impact of TP53 alteration on allogeneic hematopoietic cell transplantation outcomes for myelodysplastic syndromes [Retrospective cohort]

Highlights:

In myelodysplastic syndrome (MDS), TP53 alterations do not affect overall survival (OS) in patients undergoing haploidentical hematopoietic stem cell transplantation.

Approximately 10% of individuals with MDS have TP53 mutations, which are typically associated with poorer outcomes. Prior research showed that the prognosis of individuals with acute leukemia following haploidentical hematopoietic stem cell transplantation (haplo-HSCT) was unaffected by TP53 mutations. A recent retrospective cohort of 261 patients with MDS in China (37 patients with TP53 mutation/deletions compared to 224 with TP53 wild-type patients) evaluated the influence of TP53 alterations on the prognosis following allogeneic HSCT (allo-HSCT). The primary endpoint of this study was the 2-year cumulative incidence of relapse (CIR). Secondary endpoints were 2-year disease-free survival (DFS) and OS. TP53 status was assessed using polymerase chain reaction or next-generation sequencing in all patients before transplantation. Patients with TP53 mutations/deletions (TP53 mut/del) had a greater incidence of complex karyotype (67.5% vs. 5.8%, p < 0.001). The 2-year CIR was higher in TP53 mut/del patients than in TP53 wild-type patients (46.2%, 95% CI: 28.6–63.8 vs. 17.0%, 95% confidence interval [CI]: 7.5–26.5, p < 0.001). Additionally, patients with TP53 mut/del had a reduced 2-year OS (59.7%, 95% CI: 43.0–76.4 vs. 78.2%,  95% CI: 69.6–86.8, p < 0.001)  and worse 2-year DFS (41.8%, 95% CI: 24.6–59.0 vs. 68.9, 95% CI: 58.7–79.1, p < 0.001). In the sub-analysis of 192 patients that underwent haplo-HSCT, the 2-year DFS and 2-year CIR of TP53 mut/del patients were worse than those of TP53 wild type patients (45.4% vs. 64.2%, p = 0.002; 48.2% vs. 20.7%, p < 0.001) but the OS (66.7% vs. 75.2%, p = 0.108) was not significantly influenced by the presence of TP53 mut/del. In conclusion, TP53 mut/del were associated with higher CIR and lower DFS in MDS patients who received allo-HSCT. However, the 2-year OS was similar for those who had haplo-HSCT.

A first-in-class JAK/ROCK inhibitor, rovadicitinib for glucocorticoid-refractory or -dependent chronic GVHD [Clinical trial]

Highlights:

The dual blockade of inflammatory (JAK1/2) and fibrotic (ROCK/2) pathways is an alternative strategy that could mitigate the deleterious effects of chronic graft-versus-host disease (cGHVD).

A novel, oral dual JAK1/2 (Janus kinase 1/2) and ROCK1/2 (rho-associated coiled-coil-containing protein kinase-1/2) inhibitor, rovadicitinib is a promising therapy for the treatment of moderate or severe glucocorticoid-refractory or dependent cGVHD. A recent phase 1b/2a, multicenter, open-label study in China analyzed the recommended phase 2 dose (RP2D) and safety of two doses of rovadicitinib: 10 and 15 mg twice daily (primary endpoints) in patients with moderate or severe glucocorticoid-refractory or -dependent cGVHD. The main secondary endpoint was the best overall response (BOR) at any time up to week 24. Forty-four patients were enrolled: 29 at 10 mg rovadicitinib twice a day (BID) cohort and 15 at 15 mg BID cohort. At week 24, the BOR in the total population was 86.4%, with a complete remission rate of 9.1% and a partial remission rate of 77.3%. Correspondingly, for the rovadicitinib 10 mg BID cohort and the rovadicitinib 15 mg BID cohort, the BOR was 89.7% and 80.0%, respectively. Regarding safety, 16 patients experienced grade 3 or higher drug-related adverse events: 8 (27.6%) in the rovadicitinib 10 mg twice daily cohort and 8 (53.3%) in the 15 mg twice daily cohort. Anemia and neutropenia were present in 38.6% and 27.3%, respectively. The RP2D dose, based on data from efficacy, adverse events, and pharmacokinetic/pharmacodynamic data of the phase 1b study, was 10 mg BID. This study represents a breakthrough in targeted therapy for cGVHD and lays the groundwork for a phase 3 clinical trial. Dual JAK/STAT and ROCK2 signal pathway modulation warrants further validation based on these data.

Tuberculosis after hematopoietic cell transplantation: retrospective study on behalf of the Infectious Diseases Working Party of the EBMT [Observational study]

Highlights: Albeit a rare event, tuberculosis can develop any time after a hematopoietic stem cell transplant (HSCT) and frequently manifests as an extrapulmonary disease.

Tuberculosis (TB) in the HSCT setting is an issue that needs further examination. The frequency is variable depending on the geographical region and environmental factors. The outcomes of TB in patients after autologous HSCT (auto-HSCT) and allogeneic HSCT (allo-HSCT) need to be elucidated in the contemporary era. A retrospective cohort of 52 patients (67% male, 29% children) from 24 centers developed TB followed HSCT in Europe (Czech Republic, France, Germany, Hungary, Italy, The Netherlands, Poland, Romania, Russia, Spain, Sweden, Switzerland, and the United Kingdom), Africa (Tunisia), and Asia (Saudi Arabia and Turkey). Analysis included the attributed TB mortality and the overall survival (OS) of patients with TB (primary endpoints). Endpoints such as frequency, clinical presentation, resistance pattern, and efficacy of anti-TB treatment were also analyzed (secondary endpoints). 47 patients (90%) developed TB after allo-HSCT, and the remaining 5 (10%) after auto-HSCT. The cumulative incidence of TB-associated death was 15.9% (95% CI 7.4–27.4%) and 18.1% (95% CI 8.8–30.0%) after 6 months and 1 year, respectively. The 6-month and 1-year OS for allo-HSCT was 82.8% (95% CI 68.5–91.0) and 73.5% (95% CI 58.0–84.9), respectively, without deaths in the auto-HSCT group.

Concerning the secondary endpoints, the relative frequency of reported TB was 0.21% for allo-HSCT and 0.025% for auto-HSCT. A low frequency of screening for latent TB infection after HCT was observed (10/52, 19%). The median age at TB diagnosis was 32.0 years (range, 0.7–68.5) with a median time from HSCT to TB of 135 days (range, 16-3225), longer for pulmonary TB (P-TB). Extrapulmonary TB (EP-TB) developed solely after allo-HSCT, and fewer cases of EP-TB were diagnosed in patients with acute leukemias compared to those with P-TB (2/18, 11% vs. 18/34, 53%; p = 0.003). Data on antimicrobial susceptibility were available for 23/52 (44%) isolates, and 22% of these were resistant to at least one antimicrobial agent. In conclusion, these data support the importance of improving screening rates for TB before transplantation and identifying strains of Mycobacterium tuberculosis resistant to anti-TB drugs when choosing the appropriate treatment for this disease.

Measurable Residual Disease–Guided Therapy in Newly Diagnosed Myeloma [Prospective Clinical Trial]

Highlights:

●      In patients with newly diagnosed multiple myeloma (NDMM) who achieved negative minimal residual disease (MRD) at 10^-5 sensitivity after induction with isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) who were randomized to autologous stem cell transplant (ASCT) plus 2 cycles of Isa-KRd or 6 additional cycles of Isa-KRd, there were no differences in the rates of premaintenance MRD negativity at 10^-6 (86% vs. 84%, respectively, adjusted relative risk, 1.02; 95% confidence interval [95%CI], 0.95 to 1.10; P = 0.64).

●      In patients with NDMM who were MRD-positive at 10^-5 after Isa-KRd induction, patients treated with single ASCT had similar rates of premaintenance MRD-negativity at 10^-6 when compared to patients who underwent tandem ASCT (40% vs. 32%, respectively, adjusted relative risk, 0.82; 95%CI, 0.58 to 1.15; P=0.31).

Quadruplet induction therapy followed by ASCT has become the new standard of care for patients with NDMM. MRD negativity is an independent prognostic factor associated with both overall survival and progression-free survival, however, response adapted treatment based on MRD has not previously been reported. The MIDAS (MInimal Residual Disease Adaptive Strategy) trial is a phase III randomized trial in 72 centers in France.

Patients with NDMM received 6 cycles of Isa-KRd. Those with post-induction MRD negativity at 10^-5 were randomized to either ASCT and 2 cycles of Isa-KRd (ASCT group) or 6 cycles of Isa-KRd consolidation. Those with post-induction MRD-positivity at 10^-5 were randomized to either single ASCT plus 2 cycles (single ASCT) of Isa-KRd or tandem ASCT. The authors report here, the primary endpoint, premaintenance MRD negativity at 10^-6. At the end of induction, MRD negativity at 10^-5 was achieved in 63% of patients. Off note,19 patients (15%) did not complete the second ASCT, while >95% of in the ASCT, Isa-KRd, and single ASCT completed their planned treatment.

There were no differences in rates of pre-maintenance MRD negativity at 10^-6 in either the Isa-KRd vs. ASCT group (86% vs. 84%, respectively, adjusted relative risk, 1.02; 95%CI, 0.95 to 1.1; p = 0.64) or in the single vs. tandem group (40% vs. 32%, respectively, adjusted relative risk, 0.82; 95%CI, 0.58 to 1.15; P=0.31). In a subgroup analysis, there were no differences favoring a specific arm in either of the two randomizations with respect to age, international staging system [ISS], revised-ISS, R2-ISS, and cytogenetic risk. Off note, patients with t(11;14) had lower rates of post-induction MRD negativity at 10^-5 and were overrepresented in the tandem and single ASCT groups and had lower rates of pre-maintenance MRD negativity at 10^-6 compared to other patients without this translocation (post-induction: 24% vs. 59%, pre-maintenance: 63% vs. 78%).

The authors conclude that there were no significant differences in the rates of MRD negativity at 10^-6 with the use of single transplant compared to Isa-KRd consolidation for those with post-induction MRD negativity, or tandem vs. single for those with post-induction MRD positivity.

Intrathecal chemotherapy for ciltacabtagene autoleucel-associated movement and neurocognitive toxicity [Case Series]

Highlights:

●      Intrathecal (IT) chemotherapy with methotrexate, cytarabine, and hydrocortisone (MTX/ARA-C/Hydrocortisone) or thiothepa and hydrocortisone (Thio/Hydrocortisone) resulted in symptomatic improvement in 4/5 cases of ciltacabtagene autoleucel (cilta-cel)-associated movement and neurocognitive toxicities (MNTs).

B-cell maturation antigen (BCMA) directed chimeric antigen receptor T-cell (CAR-T) therapy has been associated with high rates of deep response in relapsed/refractory multiple myeloma but can lead (rarely) to delayed neurotoxicity, including cranial nerve palsies, neuropathy, and MNT that can be persistent. Steroids and high-dose cyclophosphamide has been used to treat such MNTs, with variable degrees of response.

The authors report on 5 cases of post-cilta-cel MNT treated with intrathecal chemotherapy after receiving systemic dexamethasone without response. Patients presented with personality changes characterized by flat affect, anhedonia, and avolition (100%), difficulty with word finding (100%), and masked facies (100%) and had a median white blood cell count (cerebrospinal fluid) of 42 /uL (range 2-140) with lymphocyte predominance (median 90%, range 89-95%); flow cytometry confirmed these were almost exclusively of T-cells .

All patients received IT chemotherapy with MTX/ARA-C/Hydrocortisone, while those with partial or no response received Thio/Hydrocortisone. Three patients had complete resolution of MNT with IT chemotherapy, one patient had a partial improvement, which then improved with high-dose cyclophosphamide, while one patient had no response despite IT treatment and cyclophosphamide. The median time to first improvement in MNT symptoms was 7 days (range 3-39 days) and to full resolution was 3 days (range 13-40 days). No toxicity from IT chemotherapy was observed, and authors highlight the safety of this approach in the treatment of MNT.

Expansions of circulating plasmablasts producing commensal-reactive IgA antibodies are predictors for chronic GVHD [Translational Study]

Highlights:

●      An increase in CD21^low plasmablasts is present before development of chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic cell transplant (allo-HCT). The immunoglobulin A antibody clones derived from this CD21^low plasmablast population bind to commensal microbiota suggesting a relationship between cGVHD and a dysregulated immune response at mucosal sites.

cGVHD is associated with significant non-relapse morbidity and mortality, often with systemic involvement. Despite traditionally being considered a T-cell driven process, B-cell dysregulation has increasingly been recognized as a contributor in the pathogenesis of cGVHD, with plasmablasts, defined as CD19⁺CD21^lowCD38 ^highCD27^high cells being elevated at cGVHD.

The authors conducted a prospective cohort study using multiparameter flow cytometry to analyze B-cell subpopulations at days 90, 180, and 356 post-allo-HCT in 108 patients. After completion of follow-up, patients were assigned retrospectively to 3 groups according to onset of GVHD: no GVHD (n=17), acute GVHD without subsequent cGVHD (n=32), and cGVHD (n=59).

The frequency of CD20^neg CD38^high plasmablasts was significantly elevated as early as 90 days post-transplant in patients who subsequently developed cGVHD compared to those without GVHD or with acute GVHD only (median 5.9% vs. 2.2% vs. 2.2% of CD19+ cells; p=0.0016 and p=0.0304, respectively). Detailed molecular analysis revealed these expanded plasmablasts were predominantly IgA-producing with molecular evidence for recent generation in mucosal sites and markers for intestinal homing, with associated mucosa associated gene expression patterns. Importantly, these IgA antibodies bind to commensal bacteria in the microbiota known to produce short-chain fatty acids.

The authors state that these data suggest that dysregulated intestinal antibody responses against commensals contribute to the pathophysiology of cGVHD.

Efficacy of Pomalidomide on Motor Performance and Functional Abilities in Patients with Steroid Refractory Chronic Graft Versus Host Disease: A Randomized Clinical Study [Randomized Clinical Trial] 

Highlights:

●      In 34 patients with steroid refractory chronic graft-versus-host disease (cGVHD) receiving pomalidomide therapy, the overall response rate for patients treated with pomalidomide was 67%. Significant improvements were observed at 6 months in hand skills (Manual Abilities Measure 36 [MAM], P = .01), upper extremity function (Disabilities of the Arm, Shoulder, and Hand [DASH], P = .01), and health-related quality of life (QoL: SF-36 Physical Component Summary score [PCS], P = .02).

●      Responders to pomalidomide therapy demonstrated better motor and functional improvement than nonresponders on most measures at 6 months, with 69% of participants reaching clinically important improvement on upper extremity disability measures.

Jorgensen et al. conducted a randomized, unblinded clinical trial at the National Institutes of Health between 2013-2016 evaluating pomalidomide's effects on motor performance and functional abilities in patients with steroid refractory cGVHD. The study enrolled 34 adults (median age 45 years, 69.6% male) with moderate to severe cGVHD, randomizing them 1:1 to low-dose (0.5 mg/d) versus high-dose (initially at 0.5 mg/d, escalating 0.5 mg every 2 weeks to a maximum 2 mg/d) pomalidomide. Twenty-three patients completed the 6-month primary endpoint analysis.

Motor assessments included Active Range of Motion (AROM), grip strength, 2-Minute Walk Test, and patient-reported measures including the Disabilities of the Arm, Shoulder, and Hand (DASH), and Manual Abilities Measure 36 (MAM). Functional abilities were evaluated using the Activity Card Sort (ACS), Human Activity Profile, and SF-36 health-related QoL, PCS. The most limiting joint There were no statistically significant differences in response or improvement between the two pomalidomide doses.

At 6 months, approximately 31% of participants achieved clinically meaningful improvement in single joint AROM. The authors conclude that pomalidomide at both dose levels may improve several aspects of motor and functional abilities in steroid refractory cGVHD, with the findings highlighting the potential utility of incorporating functional assessments like ACS, DASH, and MAM into clinical trials to better evaluate treatment efficacy in this challenging patient population.

Long-term outcomes and quality of life with treosulfan-based conditioning in hematological malignancies [Retrospective study]

Highlights:

●      In 345 patients with hematological malignancies receiving treosulfan-based conditioning for hematopoietic cell transplantation, the 5-year overall survival was 56% with a relapse-free survival of 51%, demonstrating acceptable long-term outcomes comparable to traditional busulfan or total body irradiation-based regimens.

●      Return to work rates were 43% at 1 year, 53% at 3 years, and 52% at 5 years post-transplant.

Treosulfan-based conditioning regimens have the potential of providing appropriate effectiveness with a more favorable short term toxicity profile compared to other conditioning regimens.

The authors report the results of a retrospective single-cohort at Fred Hutchinson Cancer Center analyzing long-term outcomes and quality of life in patients who underwent underwent unrelated 4/6 to 6/6 human leukocyte antigen-matched single or double cord blood, matched related donor, or matched or mismatched unrelated donor hematopoietic cell transplant for hematologic malignancies with treosulfan-based conditioning between 2005-2019. The study included 345 patients with a median age of 50.2 years (range 0.7-70.5), predominantly with acute myeloid leukemia (54%) or myelodysplastic neoplasms (31%). Patients received treosulfan intravenously at doses of 10-14 g/m² daily on days -6 to -4 (total 30 or 42 g/m²) plus fludarabine at 30 or 40 mg/m² daily on days -6 to -2, with most patients (n=255) receiving 2 Gy total body irradiation.

The 5-year chronic GVHD-,relapse-free survival was 42% and the GVHD-free, relapse-free survival was 38%. Quality of life assessments showed that while many patients returned to productive activities, 35% remained on immunosuppressive therapy at 5 years. Notably, 18 pregnancies were reported without assisted methods, with a median patient age at transplant of 40 years.

The authors suggest that treosulfan-based conditioning may offer a viable alternative to traditional regimens, with potentially improved fertility preservation, though one-third of patients continue to experience work limitations due to medical disability.