Hematologic Progression Research Articles

Kidney thrombotic microangiopathy with concurrent monoclonal gammopathy.

The concurrence of monoclonal gammopathy and TMA was suggested in a few studies. However, the complement activation was not fully studied in previous cases. In this study, we aimed to determine the complement activation in these group of patients and the association with clinical, laboratory and pathological features. Between 2007 to 2020, 20 patients with biopsy-proven renal TMA patients and monoclonal gammopathy in Peking University First Hospital were included in the study. Complement activation was tested by enzyme-linked immunosorbent assay. Associations with clinical features, pathological data, and laboratory findings were further investigated. Among renal TMA patients beyond 50 years of age, the prevalence of monoclonal gammopathy was 16.51% (18/109) which is almost 4-fold greater than the expected rate in population (4.2%). Eleven patients had acute kidney injury, and two patients required dialysis. Hematological diagnosis was consistent with monoclonal gammopathy of undetermined significance (n=10), unconfirmed MGUS (n=3), POEMS syndromes (n=4), Castleman's disease (n=2), and chronic lymphocytic leukemia (n=1). A majority of patients (84.2%) showed the activation of complement classical pathway. 15% (3/20) of patients received conservative therapy, 5% one patient received steroid only, 30% (6/20) received with immunosuppression, and 50% (10/20) received with clone-targeted chemotherapy. During 56 months Of median follow-up, ESRD developed in 2 patients, and 5 patients died mainly because of hematological progression. This study found the dysregulation of complement activation, especially the classical pathway, involved in the pathogenesis of biopsy-proven renal TMA and monoclonal gammopathy.

A phase III, randomized study of daratumumab, cyclophosphamide, bortezomib and dexamethasone (DARA-VCD) induction followed by autologous stem cell transplant or DARA-VCD consolidation and daratumumab maintenance in patients with newly diagnosed AL amyloidosis.

TPS7575 Background: Light chain (AL) amyloidosis is a plasma cell malignancy characterized by the production of amyloidgenic clonal light chains that deposit in various tissues. The addition of daratumumab to bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) has improved depth of hematologic and organ responses. However, this approach has not yet demonstrated an overall survival (OS) benefit with short follow-up. Autologous stem cell transplant (ASCT) consolidation remains safe and is associated with deep and durable hematologic responses with an 83% 2-year progression free survival (PFS) and up to 72% of patients achieving a VGPR or better, comparable to Dara-VCD (79%). In multiple myeloma, ASCT improved PFS even in patients who are MRD negative at the end of standard induction therapy. It is thus reasonable to consider that ASCT might provide similar benefits in AL patients. No randomized data exist to inform the optimal use of ASCT in the era of Dara-VCD. Methods: This randomized phase 3 SWOG led intergroup trial will accrue a total of 143 participants per arm and compare MOD-PFS (major organ deterioration progression free survival: defined as time from randomization to death, cardiac/renal progression, or hematologic progression) between participants receiving an ASCT with those receiving Dara-VCD consolidation following uniform Dara-VCD induction. A median MOD-PFS of 31 months is anticipated in the non-ASCT arm. This study has 90% power and a two-sided significance level of 0.05 to detect a hazard ratio of 0.62 corresponding to a MOD-PFS of 50 months in the ASCT arm. Important additional endpoints include OS, hematological PFS, cardiac and renal responses and progression, MRD negativity both by peripheral blood mass spectrometry and bone marrow next generation flow cytometry, delayed utilization of ASCT, and quality of life. This trial was activated on 12/1/2023. Funding: NIH/NCI/NCTN grants and in part by Janssen Pharmaceuticals. Clinical trial information: NCT06022939 . [Table: see text]

Minimal residual disease in systemic light chain amyloidosis: a systematic review and meta-analysis

PurposeMinimal residual disease (MRD) is a validated prognostic factor in several hematological malignancies. However, its role in systemic light chain (AL) amyloidosis remains controversial, and this systematic review and meta-analysis aims to fill this gap.MethodsWe searched for relevant studies on Pubmed, Embase, and Cochrane Controlled Register of Trials, nine studies involving 451 patients were included and meta-analyzed. This systematic review has been registered in PROSPERO (CRD42023494169).ResultsOur study found that in the group of patients who achieved very good partial response (VGPR) or better, MRD negativity was correlated with higher cardiac and renal response rates [pooled risk ratio (RR) = 0.74 (95% CI 0.62–0.89), 0.74 (95% CI 0.64–0.87), respectively]. Patients with MRD positivity had a higher hematologic progression rate within two years after MRD detection [pooled RR = 10.31 (95% CI 2.02–52.68)]; and a higher risk of hematologic + organ progression in the first year [pooled RR = 12.57 (95% CI 1.73–91.04)]. Moreover, MRD negativity was correlated with a better progression-free survival (PFS) [pooled hazard ratio (HR) = 0.27 (95% CI 0.17–0.45)]; but it did not significantly improve the overall survival (OS) [pooled HR = 0.34 (95% CI 0.11–1.07)].ConclusionIn AL amyloidosis, our study supports that MRD negativity correlates with higher cardiac or renal response rates and indicates a better PFS in the follow-up. However, the correlation between OS and the status of MRD is not significant.

Match Date-to-Start Date: Engaging Fellows Pre-Training

Background: The accelerating pace of progress in hematology and medical oncology is stressing an already packed curriculum. Finding time for innovative curriculum-design or to improve current curricula is challenging. We found no data in the literature about using the pre-training Match Date-to-Start Date period effectively for any educational activities of fellowship training in any discipline in the USA. Our aim was to target fellows matched to our program and see if the six months from Match Date-to-Start Date could be meaningfully utilized without interfering with their pre-training workload and activities. Method: Within four weeks following their match date, the four incoming fellows received a questionnaire. The questionnaire targeted six key research variables, encompassing their field of interest, preferred type of research, desired mentorship, self-assessment of current skills, and the amount of time they were willing to dedicate per week to any fellowship program-related recommended reading until the official start date of July 1. We sent each fellow one email each week with one or two PDFs as educational material. Each fellow received a list of potential mentors with mentor-CVs and information about each mentor's area of focus. Each fellow could choose up to two mentors to interview with. Using their responses as a guide, we arranged 30-minute video meetings between the fellows and their choice of potential mentors. Prior to the start-date, we administered a questionnaire to evaluate the effectiveness and impact of this process. Results: A total of 4 fellows were given a questionnaire post-match to gather their interests, skill set and time willing to dedicate to research. The responses were received in less than 24 hours (table 1). 2/4 chose to focus their research and scholarly activities in medical oncology/solid tumors and the other two chose to focus on malignant hematology. ¾ did not have a chosen mentor already. For their self-reported skills, 75% felt confident in abstract writing and poster presentation while only 50% felt confident in manuscript and grant writing skills. All 4 of them were willing to Commit 1-3 hours match date to start date on items related to research and scholarly activity. By April, each of the four fellows had been successfully paired with a mentor of their choice. At the end of the study period, the pre-start-date questionnaire demonstrated that all 4 fellows strongly agreed that that this Match Date-to-Start Date program was helpful, was not disruptive, and liked the process of choosing their mentor prior to starting their training. Conclusion: This program was designed as a pioneering initiative to optimize the time between the match date and the start date of fellowship training for incoming hematology oncology fellows. Its primary objectives were met: to facilitate a seamless transition for fellows, providing them with valuable opportunities to connect with mentors who share their research interests, enabling them to make informed choices. Additionally, we have implemented a semi-annual follow-up system to document the progress, challenges faced, and gather feedback on how to enhance and refine the program.

Daratumumab-Based Regimens Versus Cybord in Newly Diagnosed Patients with AL Amyloidosis and IIIb Cardiac Stage: A Matched Case-Control Study

Background: Improving the outcomes of light chain (AL) amyloidosis patients and advanced heart involvement, IIIb Mayo cardiac stage, is an unmet need. The standard front-line treatment has been cyclophosphamide-bortezomib-dexamethasone (CyBorD) until the approval of daratumumab with CyBorD (Dara-CyBorD) in 2021, which significantly improved the rate of hematologic response (HR) as reported by the ANDROMEDA trial. However, stage IIIb patients were excluded from the study and the best upfront treatment strategy in these patients remains to be clarified. For this reason, daratumumab was not licensed for use in stage IIIb patients in many countries. Preliminary data of the ongoing EMN22 phase II multicenter study (NCT04131309), that specifically addresses this issue using daratumumab monotherapy, are promising. Chakraboty et al. reported that Dara-CyBorD is effective in inducing profound hematologic response, at least a very good partial response (VGPR), in treatment-naïve patients with IIIb AL amyloidosis. Similar results were reported by Theodorakakou et al. using different daratumumab combinations. Finally, in a study conducted by Oubari et al. daratumumab-based regimens were associated with better clinical outcomes compared to others treatments. However, all available data on daratumumab in stage IIIb patients derive from uncontrolled studies or lacked a matched or stratified control group. We designed the present retrospective case-control study to assess the efficacy of daratumumab-based therapies versus CyBorD regimens as upfront treatment for newly diagnosed AL amyloidosis with IIIb cardiac stage. Methods:the whole study population comprises 62 matched newly diagnosed patients with IIIb stage AL amyloidosis evaluated in our center between 2012 and 2022. The daratumumab cohort is composed of all the 31 consecutive subjects treated with daratumumab-based regimens between 2021 and 2022. Thirteen patients (41%) received daratumumab in combination with bortezomib [11 (35%) associated with melphalan and dexamethasone; 2 (6%) Dara-CyBorD], 11 (35%) with lenalidomide and 7 (22%) were treated with daratumumab monotherapy. They were matched with 31 controls selected from a total of 71 subjects treated with CyBorD. Patients and controls were matched for age, estimated glomerular filtration rate, N-terminal pro-brain natriuretic peptide, free light chain and bone marrow plasma cell. Hematologic response was assessed according to the International Society of Amyloidosis criteria. The analysis of response was by intent-to-treat: patients who died before response evalutation were considered non responders . PFS is defined as the time from diagnosis to any one of the following events, whichever comes first: death, starting a second line of therapy, organ or hematologic progression as per consensus guidelines. Results:Patients' characteristics are listed in Table 1. Median follow-up of living patients was 20.5 months (95% CI: 14.3 - 55.9 months). Median OS was 4.6 months (95% CI: 3 - 6.3 months), and patients of the daratumumab cohort had a significantly prolonged OS (6.7 vs 4 months; p=0.032, Fig. 1). No differences in early mortality rate, within 3 months from diagnosis, were observed between the two cohorts (32% vs 35%, p=0.796). At three months, the overall HR rate to daratumumab was 50% [complete response (CR) 12%, VGPR 29%, partial response (PR) 9%] as compared with 21% (CR 6%, VGPR 9%, PR 6%) of the control group, p=0.021. A higher proportion of ≥VGPR was observed in the daratumumab cohort (41% vs 16%; p=0.029). Cardiac response rate was significantly more frequent in patients treated with daratumumab [8 (25%), 3 cardiac VGPR and 5 cardiac PR] compared to controls [1 (3%) cardiac PR], p=0.014. A significantly prolonged PFS was observed in patients receiving daratumumab compared to CyBorD (5 vs 2.4 months; p=0.017). Conclusions: This matched case-control study shows that even in stage IIIb patients the addition of daratumumab to CyBorD results in higher rates of deep hematologic response. This is associated with higher cardiac response rates and prolonged OS and PFS. Although the outcome of stage IIIb patients remains dismal, Dara-CyBorD was able to improve response rate and survival in these severely compromised subjects. Taken together these observations encourage the use of daratumumab combinations also in stage IIIb patients with AL amyloidosis.

Belantamab Mafodotin in Relapse/Refractory AL Amyloidosis- Real-Life Multi-Center Experience

Introduction: Bortezomib and daratumumab revolutionized the therapy for AL amyloidosis (AL). However, relapsed/refractory AL resistant to both drugs is an unmet clinical need, with limited options due to the frailty of these patients and paucity of prospective data. The safety profile and efficacy of belantamab mafodotin (BLM) in multiple myeloma (MM) are well known. In contrast, published data for AL are currently limited to case series of 6 (Zhang, Ann Hematol. 2022) and 12 patients only (Khwaga, Blood Cancer J. 2022). Here, we report a multicenter real-world data on 12 AL patients treated with BLM and compare these to the prior reports. Methods: We retrospectively identified all AL amyloidosis patients who received BLM outside a clinical trial, between Feb 2020-Sep 2022. The diagnosis, staging, hematologic and organ responses and progression of AL were evaluated according to consensus criteria. Event-free survival (EFS) was defined as the time from the first day of BLM administration to hematologic progression or therapy change for inadequate response or death. Results: Twelve AL patients from 5 centers in Israel and Italy were included. The median age at BLM initiation was 66 y (range 54-70). The most common FISH aberrations were 1q gain in 8 patients (67%) and t(11;14) in 5 (42%). All patients except one had cardiac involvement (92%) and 9 (75%) had renal involvement. The median number of prior lines of therapy was 3 (range 2-9). All patients previously received bortezomib, an alkylator and daratumumab, 11 (92%) received lenalidomide, 10 (83%) received pomalidomide and 9 (75%) underwent prior autologous transplant. Seven patients (58%) had Eastern cooperative oncology group performance status (ECOG-PS) of at least 2 at BLM initiation and half of the patients had AL Mayo stage of at least 3a. Most patients (10/12) received BLM as a single agent at 2.5mg/kg q3 weeks. The overall hematological response rate (ORR) to BLM was 75% (9/12), including 5 patients with complete response, 3 with very good partial response, and 1 with partial response (Figure 1). Detailed biomarker-based evaluation of organ responses was missing in many patients, yet, of 4 evaluable patients, 3 cardiac responses were observed. An additional patient had marked clinical improvement of heart failure. Four renal responses (out of 5 evaluable patients) and 2 hepatic responses (out of 2 evaluable) were also observed. With a median follow-up of 13.0 months (m) from initiation of BLM therapy (range 1.1-33.8m), the median EFS was 22.3m and the median OS was 28.8m. At data cutoff 6/12 (50%) were still on therapy, 9/12 patients (75%) were alive, all 3 deaths were due to heart disease. Seven patients (58%) had at least one grade 3 toxicity, included mostly infections/corneal toxicity. Apart from one event of grade 3 thrombocytopenia, there were no grade ≥3 hematological toxicities. No grade 4/5 toxicities were observed. Most patients (10/12, 83%) had corneal toxicity (6 patients- grade 1-2; 4 patients- grade 3), and dose reductions/delays were frequent (4/12 and 6/12, respectively). However, 7/10 patients with corneal toxicity improved overtime, no permanent visual disabilities were observed and only one patient stopped BLM due to keratopathy. Discussion: While BLM provides an ORR of 30-45% in triple-refractory MM patients, it might have a greater efficacy in AL patients. The ORR in our heavily pre-treated AL patients, as well as in other studies (2 small, retrospective + preliminary results of the EMN27 prospective study (Kastritis, EHA conference 2023) approached 60-83%, and the EFS was also encouraging. This difference may be attributed to the lower burden of disease in AL compared to MM. Alternatively, AL plasma cells may be more sensitive to BLM, in a mechanism that still merits further exploration. Corneal toxicity was similar to what was seen in MM, and overall manageable. Hematological toxicity was significantly milder than that observed in MM, probably related to the better marrow reserve in AL. Conclusions: BLM, being an off-the shelf immune therapy, with acceptable toxicity even in frail patients, can be a valuable option in AL, with a high ORR, and a signal for durable responses and high-quality organ responses in these patients.

Efficacy and Safety of Belantamab Mafodotin Monotherapy in Patients with Relapsed or Refractory Light Chain Amyloidosis: A Phase 2 Study By the European Myeloma Network

Introduction Belantamab mafodotin (belamaf) targets B-cell maturation antigen (BCMA) expressing plasma cells (PCs) and is approved for heavily pretreated patients (pts) with relapsed/refractory (RR) multiple myeloma. Clonal PCs in light-chain (AL) amyloidosis also express BCMA; thus, belamaf could be a treatment option for RRAL amyloidosis pts. We present an interim analysis of the prospective EMN27 study assessing efficacy and safety of belamaf monotherapy in RRAL amyloidosis pts. Methods The ongoing prospective, open-label, multinational, phase 2 EMN27 study (NCT04617925) aims to enroll 36 adult pts with RR (defined as ≥2 cycles of therapy directed against PC clone) AL amyloidosis, adequate hematologic, hepatic, renal, and cardiac function, and ECOG ≤2. Pts at Mayo cardiac stage 3B or with previous exposure to anti-BCMA agents are excluded. Monotherapy with belamaf at a starting dose of 2.5 mg/kg (or 1.92 mg/kg for toxicity) is administered by intravenous infusion every 6 weeks for up to 8 cycles. Pre-planned study analyses included an interim safety (after first 6 pts received ≥1 treatment cycle) and an efficacy analysis (after 13 pts were enrolled). Outcomes of both were favorable and study enrollment is ongoing. This descriptive analysis included pts initiating treatment ≥3 months before 31/05/2023 (cutoff date). Results Twenty-eight pts have been included in this analysis (median [range] age: 66 years [46-80]; male: 16 [57%]). At screening, 5 (18%), 15 (54%), and 8 (29%) pts were rated as Mayo stages I, II, and IIIA, respectively. Most pts had cardiac involvement (22, 79%), followed by those with renal (17, 61%) and peripheral nerve (6, 21%) involvement. Most pts (21, 75%) had New York Heart Association class II symptoms and the median N-terminal pro-brain natriuretic peptide, high-sensitivity troponin T, and difference in involved and uninvolved free light chain (dFLC) were 1,393 ng/L (90-7,270), 34 ng/L (3-116), and 119 mg/L (38-2,791), respectively. The median number of prior treatment lines was 4 (1-10). Twenty-one (75%) pts had previously received daratumumab (dara) (12 [42.9%] dara refractory pts), while 24 (86%) pts had previously received bortezomib, both with median of 4 (1-10) prior treatment lines. At cutoff, 4 (14%) pts were continuing therapy, 21 (75%) pts discontinued (disease progression/inadequate response: 9 [32%]; adverse events [AE]: 8 [29%]; withdrew consent: 1 [4%]; death 3 [11%]), and 3 (11%) pts completed treatment. Median belamaf cycles administered were 3 (1-8). Ninety-five belamaf doses were given (2.5 mg/kg: 72, 1.92 mg/kg: 23). Eleven (39%) pts had 23 belamaf dose holds due to AE/SAE, with median delay of 21 (7-128) days from planned administration. At a median follow up of 16 months (4-26), the overall hematologic response (≥partial response [PR]) and very good partial response (VGPR) rates were 54% (15 pts) and 32% (9 pts), respectively ( Table). Median times to first hematologic response and VGPR were 15 (7-148) and 43 (15-106) days, respectively ( Table). Median duration of hematologic response (time from first response to hematologic progression or treatment/disease-related death) was not reached either for all pts or for pts pre-treated with dara. At 1 and 3 months, the respective overall hematologic responses were 39% (11 pts) and 50% (14 pts). Respective rates for pts with prior dara exposure were 29% (6 pts) and 43% (9 pts). For all pts, 3-month organ response rate was 14% (4 pts; Table). All pts experienced >1 AE (ocular AEs: 27 [96%] pts; hematologic toxicity: 8 [30%] pts; cardiac disorders: 7 [25%] pts); no new cardiac or renal toxicity observed. Three (11%) pts had a fatal AE, all considered unrelated to belamaf. Twenty-two (79%) pts had visual acuity reduced (grade [Gr]1: 3 (11%); Gr2: 8 [29%]; Gr3: 10 [36%]; Gr4: 1 [4%]), 22 (79%) keratopathy (Gr1: 10 [36%]; Gr2: 8 [29%]; Gr3: 4 [14%]; Gr4: 0 [0%]), and 7 (25%) visual impairment (Gr1: 1 [4%]; Gr2: 4 [14%]; Gr3: 1 [4%]; Gr4: 1 [4%]). Conclusions In heavily pretreated pts with RRAL and limited treatment options, belamaf monotherapy achieved an overall hematologic response of 54% without unexpected toxicity. Results suggest belamaf could be a treatment option for RRAL amyloidosis, a difficult to treat population. Further evaluation of belamaf in combination with other active agents could allow longer intervals (i.e., 8-12 weeks) between belamaf doses, which has shown to reduce ocular toxicity, while maintaining efficacy.

Efficacy and safety analysis of a combination regimen with BCL-2 inhibitor in relapsed/refractory primary systemic light chain amyloidosis with t(11;14) from a single center

Objective: To explore the efficacy and safety of BCL-2 inhibitor-based treatment in patients with relapsed/refractory t (11; 14) primary systemic light chain amyloidosis. Methods: This was a retrospective case series study. Ten patients with relapsed/refractory t(11;14) primary systemic light chain amyloidosis who had all received treatment with a combination regimen including the BCL-2 inhibitor venetoclax from January 2018 to November 2022 at the Hematology Department of Peking University People's Hospital were included. Adverse events, and hematological and organ responses were evaluated. Results: The median age of the ten enrolled patients was 59 (range 41-78) years, and the male to female ratio was 8∶2. Except for one patient, a very good partial or better response was achieved in 8/9 patients and one patient obtained a partial response. The overall response rate was 100%. The median time to achieve a hematological response was 60 (range 24-236) days. At least one organ response was observed in 7/9 patients. With a median follow-up of 18 months, one patient experienced hematological progression and one patient died. Grade 3 adverse events included lymphocytopenia (3 cases), anemia (1 case), diarrhea (1 case), and appendicitis (1 case). One patient died of pulmonary fungal infection two months after completion of treatment, which was not excluded as being treatment related. Conclusion: A combination regimen including BCL-2 inhibitors in patients with relapsed/refractory t(11;14) primary systemic light chain amyloidosis is a potentially safe and effective treatment option that warrants further investigation.

Updated OS of patients with AL amyloidosis after CAEL-101.

8026 Background: Morbidity and mortality remain high in immunoglobulin light chain (AL) amyloidosis due to organ involvement despite hematologic remission. Few anti-amyloid fibril therapies for AL amyloidosis exist. We previously published the results of the phase 1a/1b study of CAEL-101 in AL amyloidosis showing significant improvement in organ response rates.1 We report long-term outcomes. Methods: Patients enrolled in NCT02245867 with relapsed/refractory AL amyloidosis received in phase 1a, a one-time dose-finding CAEL-101 infusion and in phase 1b, 4 weekly CAEL-101 infusions with preplanned dose escalation. Patients were evaluated for organ response for 12 weeks after last infusion. We extracted clinical, laboratory, and pathology data regarding clinical course beyond 12 weeks after last treatment. We performed a review of all AL amyloidosis patients at our center not treated with CAEL-101 1/01/2012-12/30/19 as clinical comparisons. Results: 22 patients were enrolled in CAEL-101. 5 patients were treated in both phase 1a and phase 1b. With median follow-up of 81.3 months (IQR 60.4-87.7), long term follow-up data are available for 19/22 patients. 5 patients died during long term follow-up: 3 from progressive AL amyloidosis; 1 from organ transplantation complication; and 1 from venous thromboembolism sequelae. Among patients with organ data available, 10/17 had hematologic progression and received next line therapy. 5/17 patients had organ progression. All patients with organ PD had previous/concomitant hematologic PD. Median OS was not reached; median organ PFS was 93.3 months (38.9-NR). No delayed adverse events occurred. Comparison with historical control groups revealed trends toward improved OS: HR 0.42 (0.09-1.81 p=0.23) in all comers AL amyloid controls, and HR 0.20 (0.03-1.16 p=0.07) in cardiac controls. Kaplan-Meier analysis and Cox regression were performed. Conclusions: Patients with relapsed/refractory AL amyloidosis who received a low cumulative amount of the novel anti-amyloid CAEL-101 in a phase 1a/1b study had lengthy overall and progression-free survival compared to historical controls. Patterns of organ progression after initial response may reflect intrinsic differences in organ vulnerability. The CAEL101-301 and CAEL101-302 phase 3 clinical trials are underway to confirm these findings. Reference: 1. Edwards CV, Rao N, Bhutani D, et al: Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. Blood 138:2632-2641, 2021. [Table: see text]

Outcomes of individuals with clonal hematopoiesis evaluated at a cancer center.

7072 Background: Clonal hematopoiesis (CH) refers to the presence of somatic mutations in individuals without overt hematological disorders. CH, including CH of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), is associated with hematologic malignancies and other systemic comorbidities. There are currently no established guidelines regarding the optimal monitoring and management of patients with CH, and the impact of CH in patients with concomitant underlying malignancies remains unknown. Methods: Patients seen at a tertiary cancer center with at least 1 somatic mutation detected by next generation sequencing on bone marrow aspirate or peripheral blood between January 2015 and March 2021 were included. Patients with donor-derived CH or any morphologic evidence of a myeloid neoplasm were excluded. Results: We evaluated 78 patients – 76% had a history of malignancy and 73% had other comorbidities. The mutations most frequently observed were DNMT3A (40%), TET2 (31%), TP53 (26%), and ASXL1 (18%). The median overall survival for all patients was not reached (2-year survival rate of 79%). Most deaths were related to primary malignancies (35%), comorbidities (20%), or myeloid neoplasms (20%). Due to concomitant use of antineoplastic therapy and other causes of cytopenia in 19 patients, we further categorized patients into 4 groups: CHIP on treatment (CHIP-T), other CHIP (CHIP-O), CCUS on treatment or with a non-myeloid hematologic malignancy (CCUS-T), and other CCUS (CCUS-O). Transformation to a myeloid neoplasm occurred in 12 patients (15%). The 3-year cumulative incidence of transformation was higher in CCUS-O (24%) and CCUS-T (21%) compared to the CHIP group (6%, p = 0.48). On univariate analysis, increasing age, variant allele frequency (VAF) ≥ 0.2, hemoglobin < 10 g/dL, and any chromosomal abnormalities were associated with higher risk for transformation. By multivariate analysis, transformation was only significantly associated with VAF ≥ 0.2 (hazard ratio (HR) 18.25; 95% confidence interval (CI): 3.59, 92.73; p = 0.0005) and hemoglobin < 10 g/dL (HR 15.62; 95% CI: 3.29, 74.05; p = 0.0005). Conclusions: CH in predominantly cancer patients is associated with cardiovascular disease and transformation to myeloid neoplasms, especially in those with higher mutational burdens and anemia. However, patients die more frequently from their primary malignancy or comorbidities than from a myeloid neoplasm. Close monitoring of hematologic progression and extra-hematologic manifestations of CH is crucial. Further investigation into the identification of individuals at high risk of myeloid transformation and potential early therapeutic interventions for this population is warranted.

Prognostic impact of translocation t(11;14) and of other cytogenetic abnormalities in patients with AL amyloidosis in the era of contemporary therapies.

Translocation t(11;14) is the most common cytogenetic abnormality in patients with systemic AL amyloidosis with prognostic and therapeutic relevance, which has not been clearly defined in the most recent therapeutic era. We assessed its prognostic role in 146 newly-diagnosed patients who received novel agent-based treatment combinations. Event-free survival (EFS), a composite endpoint defined by hematological progression, start of a new treatment-line or death, and overall survival (OS) were the primary endpoints. Half of the patients had at least one FISH abnormality; 40% had t(11;14) which was inversely associated with other cytogenetic abnormalities. At 1, 3, and 6-month landmarks, hematologic response rates were numerically but not statistically higher in the non-t(11;14) group. Patients with t(11;14) were more frequently switched to second-line treatment within 12 months (p = .015). At median follow-up of 31.4 months, t(11;14) was associated with shorter EFS [17.1 (95% CI 3.2-10.6) vs. 27.2 months (95% CI 13.8-40.6), p = .021] and retained its prognostic significance in the multivariate model (HR:1.66, p = .029). The effect on OS was neutral, possibly due to the use of effective salvage therapies. Our data support the use of targeted therapies for patients with t(11;14) to avoid delays in the achievement of deep hematologic responses.

Colonic amyloidosis: Rare endoscopic findings mimicking a depressed neoplastic lesion.

A colonic depressed lesion was found in a 77-year-old man and suspected as a neoplastic lesion using conventional endoscopy. Magnifying endoscopy, however, did not support it and biopsy revealed the lesion to be AL amyloidosis.

Somatic genetic alterations predict hematological progression in GATA2 deficiency.

Germline GATA2 mutations predispose to myeloid malignancies resulting from the progressive acquisition of additional somatic mutations. Here we describe clinical and biological features of 78 GATA2-deficient patients. Hematopoietic stem and progenitor cell phenotypic characterization revealed an exhaustion of myeloid progenitors. Somatic mutations in STAG2, ASXL1 and SETBP1 genes along with cytogenetic abnormalities (monosomy 7, trisomy 8, der(1;7)) occurred frequently in patients with GATA2 germline mutations. Patients were classified into three hematopoietic spectra based on bone marrow cytomorphology. No somatic additional mutations were detected in patients with normal bone marrow (spectrum 0), whereas clonal hematopoiesis mediated by STAG2 mutations was frequent in those with a hypocellular and/or myelodysplastic bone marrow without excess blasts (spectrum 1). Finally, SETBP1, RAS pathway and RUNX1 mutations were predominantly associated with leukemic transformation stage (spectrum 2), highlighting their implications in the transformation process. Specific somatic alterations, potentially providing distinct selective advantages to affected cells, are therefore associated with the clinical/hematological evolution of GATA2 syndrome. Our study not only suggests that somatic genetic profiling will help clinicians in their management of patients, but will also clarify the mechanism of leukemogenesis in the context of germline GATA2 mutations.

Advances, challenges and progress in pediatric hematology and oncology.

National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland, NIH, USA Correspondence to Brigitte C. Widemann, National Cancer Institute, Center for Cancer Research, Pediatric Oncology Branch, Bethesda, Maryland, USA. E-mail: [email protected]

Thrombosis with Non-Proliferative Complete Blood Count Indicative of Underlying Myeloproliferative Neoplasm, Sythrom, a Study on Behalf of the FIM Group

Introduction Thrombosis is the main cause of morbidity in myeloproliferative neoplasms (MPN) and can be the mode of revelation of these malignant diseases. Most of them are characterized by specific driver mutations such as JAK2 V617F, CALR or MPL. An idiopathic or atypical thrombotic event justifies looking for MPN by searching these MPN-related mutations, even in the absence of myeloproliferative features on the complete blood count (CBC). This is especially crucial in case of splanchnic and cerebral thromboses, but not only. In this context the diagnosis of MPN and the choice of treatment are made difficult by the absence of increased blood counts. Objectives - To constitute an observational cohort of patients (pts) presenting an arterial or venous thrombotic event leading to a suspicion of MPN without signs of myeloproliferation in CBC. - To study the characteristics of pts at diagnosis, the rate of recurrence of thrombosis and the rate of hematological progression. Patients and method Inclusion criteria were as follows: i)-diagnosis of an arterial or deep venous thrombotic event, ii)-CBC not suggestive of polycythemia vera (PV), essential thrombocythemia (ET) or myelofibrosis (MF) (CBC below WHO 2016 thresholds) but iii)-detection of a molecular abnormality (JAK2, CALR or MPL driver mutations) and/or an abnormality on bone marrow trephine in favor of MPN and/or spontaneous progenitor growth. Data were collected retrospectively and prospectively. The study is registered on ClinicalTrial.gov (NCT04539678). Results Between 05/2019 and 06/2022, the participation of 31 centers in France and Switzerland allowed the collection of data from 216 pts. The analysis is presented for 208 pts after exclusion of incomplete non-evaluable cases (n=5) or those not meeting inclusion criteria (n=3). The M/F sex ratio was 1.3 with a median age of 55 years (22-91) at the date of molecular testing. Inaugural thrombosis was venous (80%) or arterial (20%) and involved either splanchnic (50%), cerebral (24%), other locations (23%) or multiple territories (3%). Median CBC values were hemoglobin 14 g/dL, hematocrit 43%, platelets 298x109/L and leukocytes 7,1 x109/L. Pts had either a driver mutation of JAK2 V617F (n=201), CALR (n=2) or MPL (n=2), or none of these but spontaneous progenitor growth (n=3). According to WHO criteria, the diagnoses retained were MPN in 91 (44%) cases (including 26 PV, 4 MF and 61 unclassifiable MPN), while 38 pts (18%) lacked MPN criteria and 79 (38%) were not assessable (no trephine). A clinical follow-up of at least 3 months was available in 197 pts, with a median of 61 months (range 3 months - 36 years). Recurrent thrombosis occurred for 42 pts (21%, respectively 24% of initially arterial and 19% of initially venous). Recurrence was splanchnic for 13 pts (31%). The median delay of recurrence was 37 months (12 days - 18 years) after the thrombotic event that led to a suspicion of MPN. Recurrence occurred more often in pts with initially non-splanchnic thrombosis (30% vs. 13% p=0.004). Thrombosis recurrences were not significantly different between pts classified as MPN and those without MPN criteria (18% vs. 30% p=0.1). Hematological progression was observed for 27 pts with a median delay of 31 months (1 - 105) since thrombosis. According to WHO MPN criteria, they were 9 PV, 14 TE and 4 MF. Pts with thrombotic recurrence more frequently presented hematological progression or died (31 month progression-free survival [PFS] 85% vs 94% p=0.008). PFS was significantly reduced in cases of initially non-splanchnic thrombosis (86% vs 97% at 31 months p<0.0001). An explanation could be that pts with splanchnic thrombosis were more frequently treated with cytoreductive agents (CRA) (71% vs 41% p=0.03). Analysis of the effect of antithrombotic therapy is ongoing. Conclusion Thrombosis cases with a non-proliferative CBC but with MPN driver mutations leading to MPN suspicion constitute a heterogeneous group of pts, with many cases of non-splanchnic involvement. The latter pts show more frequent thrombotic recurrences and hematological progression than pts with splanchnic involvement. The role of cytoreduction and antithrombotic therapies needs to be explored in this context.

Using a Humanized Animal Model to Determine the Minimum JAK2V617F Mutant Allele Burden Required to Generate MPN Pathologies

Myeloproliferative neoplasms (MPNs) are clonal hematological diseases driven by somatic mutations acquired in hematopoietic stem cells (HSCs) and characterized by the deviant, unregulated proliferation of one or more myeloid lineages. Chronic MPN can present as polycythemia vera (PV; excess erythrocytes), essential thrombocythemia (ET; excess platelets), or myelofibrosis (MF; bone marrow fibrosis). More than 300,000 patients are currently living with an MPN diagnosis in the United States. The JAK2V617F variant is an acquired somatic mutation recurrently found in MPN patients and is used as a diagnostic marker along with increased hematocrit, increased hemoglobin, and adverse thrombotic events. In MPN patients, the frequency of JAK2V617F mutant cells varies widely but is known to induce an MPN phenotype with both high (>50%) and very low (<5%) variant allelic frequency (VAF). The reason for this is currently unknown. Most JAK2-mutant animal models model a VAF which is much higher than the lower end of detectable VAFs found in MPN patients. This results in a very limited understanding of what the minimal mutant cell burden required for disease manifestation is. The understanding of genotype/phenotype relationships in patients with low JAK2V617F VAF chronic MPN is paramount to our understanding of this disease and its hematological progression. To this end, we have designed a clinically relevant, humanized mouse model wherein we employ CRISPR and homology directed repair (HDR) via a single stranded oligo donor nucleotide sequence (ssODN) to knock-in the JAK2V617Fmutation at the endogenous locus of human cells at low VAF. In addition, a synonymous JAK2V617V mutation was introduced via CRISPR/ssODN in parallel cells to serve as a control tracked by VAF alongside the VAF of JAK2V617F in their corresponding cohorts. The respective ssODNs were nucleofected into either umbilical cord blood (UCB) derived CD34+ cells or healthy adult bone marrow (BM) derived CD34+ cells to investigate the possibility that developmental age is a variable in low JAK2V617F VAF inducing a clinical MPN phenotype. After nucleofection, 20,000 CD34+ cells were intra-tibially transplanted into sub-lethally irradiated (250 rads) NSGS mice. The low cell input was utilized to limit engraftment and initial disease burden of mutant cells. Effect was measured by mutant allele burden by droplet-digital PCR (ddPCR) analysis, flow cytometry at selected timepoints to track human cell engraftment, spleen weight, and complete blood count (CBC) analysis including hematocrit, hemoglobin, white blood cells, and platelets. At 4 months post-transplant, peripheral blood hCD45+ engraftment across all cohorts averaged less than 3%. Average VAF of circulating hCD45+ cells increased in both JAK2V617F cohorts 5 months post-transplant compared to day 0 post nucleofection. Notably, overall JAK2V617F VAF in each sample remained <5% when adjusted to include both human and mouse derived peripheral blood cells. Remarkably, both hematocrit (p= .037 in UCB cohorts and p=.0096 in BM cohorts; Figure 1A) and hemoglobin (p=.046 in UCB cohorts and p=.0026 in BM cohorts; Figure 1B) were significantly elevated in both JAK2V617F cohorts compared to their respective JAK2V617V controls, while white blood cell and platelet counts remained unchanged within normal ranges. In addition, spleen weights were significantly increased in both JAK2V617F cohorts compared to their respective controls. These data demonstrate a successful clinical model of MPN which induces a classical MPN phenotype where a low VAF of JAK2V617F corresponds with a significant increase of hematocrit, hemoglobin, and spleen weight in a humanized mouse model compared to relevant controls. In addition, we demonstrate that while engraftment due to low hCD34+ cell input remains low after 4 months, the VAF of JAK2V617F within the hCD45+ sub- population increases. This successfully enables the overall VAF contributing to the MPN phenotype to remain at clinically relevant lower levels compared to other models with much higher VAF contributions. We believe this model to be of high clinical relevance into the investigation of how low JAK2V617F burden relates to disease development and progression in MPN patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Single Center Real World Data That Compares Autologous Stem Cell Transplant in the Era of Anti-CD38 Monoclonal Antibody Based Treatments for AL Amyloidosis

Introduction: Systemic AL amyloidosis is a plasma cell disease characterized by the deposition of insoluble amyloid fibrils causing organ dysfunction and death. Results from the ANDROMEDA study showed that the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone (VCD) was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. In our single-center retrospective real-life case series, we aimed to evaluate the role of AHCT in the era of Anti-CD38 monoclonal antibody based treatments for AL amyloidosis Patients and Methods: One hundred and two consecutive patients newly diagnosed with AL amyloidosis at our center between 2007-2022 were included retrospectively. The F/M ratio was 50/52 The median age was 61 years (range:31-85), and the median follow-up was 11.8 months (range: 1-100 months). There were 68 (66%) patients with cardiac involvement and 79 (76.7%) patients with renal involvement at the time of diagnosis. Among all patients, 33% had stage 0-1, 60.2% ≥ stage 2 cardiac involvement. At the time of diagnosis, 61.2% of the patients had renal stage 2-3 disease. Fourthy-six patients (44.7%) patients had stages III and IV according to the Revised Mayo Clinic Staging System. Induction treatments that were used in our center were melphalan-dexamethasone(2007-2014), bortezomib-dexamethasone (2007-2022), VCD (2007-2022), Daratumumab-VCD (2018-2022) and up-front AHCT for transplant-eligible patients (2007-2022). Results: Eighty of 102 patients (78.4%) underwent AHCT and post-transplant 41 patients achieved ≥VGPR but 43 patients deceased during post-transplant follow-up. Among patients who received daratumumab-based induction treatment without AHCT consolidation, 11/20 patients achieved ≥VGPR and none of these patients relapsed. In patients who received daratumumab-based induction treatment renal and cardiac responses were observed in 50% and 60%, respectively. Death was significantly lower among patients with Mayo Clinic Risk Stage 3-4 who received daratumumab (20% (3/15) vs 71% (22/31); p=0.002). Median overall survival was 56.8 months (95% CI 22.7-90.9) and the probability of 2-years OS was 56.2%. There were significant differences in median OS according to daratumumab administration (NR vs 23.3 mos; p=0.015) (Figure-1). Patients who had received daratumumab as an induction treatment without AHCT consolidation (n=20) have displayed prolonged OS compared to others (n=80) (NR vs 32.6 mos (95% CI 0-71.5); p=0.1) (Figure-2). There were no significant differences in 2-years PFS between the two groups but it's important to note that no progression was seen in the daratumumab group (Figure-3). If Cox proportional hazards model including Revised Mayo Clinic Stage, w/wo AHCT, and w/wo Daratumumab was used, only Daratumumab administration was associated with better PFS (HR: 18.8 (95% CI: 3.3-108.8); p=0.001). Conclusion: From the prognostic point of view, our results based on real-world AL amyloidosis experience showed the improvement in OS with daratumumab-based treatments even in advanced stages of the disease. In addition, all patients rapidly achieved hematological response that deepened over time, and also cardiac and the renal response was also observed in a substantial proportion of our cohort. The data presented here add to the growing body of literature supporting the delayed use of AHCT in patients with AL amyloidosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pulmonary hypertension is associated with poor cardiovascular and hematologic outcomes in patients with myeloproliferative neoplasms and cardiovascular disease.

Cardiovascular events and hematologic progression to myelofibrosis or leukemia are leading causes of morbidity and mortality among patients with myeloproliferative neoplasms (MPN). Pulmonary hypertension (PH) is also associated with MPN and cardiovascular disease (CVD), though its prognostic significance in MPN is not well characterized. Our primary objective was to investigate the effect of PH, defined as right-ventricular systolic pressure (RVSP) ≥ 50mmHg on echocardiogram or mean pulmonary artery pressure (mPAP) ≥ 20 on right heart catheterization, on cardiovascular and all-cause mortality and hematologic progression in patients with MPN and CVD (atrial fibrillation, heart failure hospitalization, and myocardial infarction after MPN diagnosis). Of the 197 patients included (86 ET, 80 PV, 31 PMF), 92 (47%) had PH and 98 (50%) were male. All-cause mortality (58 vs 37%, p = 0.004), cardiovascular death (35 vs 9%, p < 0.0001), and hematologic progression (23 vs 11%, p = 0.037) occurred more frequently in patients with PH. Multivariable competing-risk and proportional hazards regression showed that PH was associated with increased risk of all-cause death (adjusted hazard ratio [HR], 1.80, 95% CI 1.10-2.93), CV death (adjusted subdistribution HR 3.71, 95% CI 1.58-8.73), and hematologic progression (adjusted subdistribution HR 1.99, 95% CI 1.21-3.27).

Advances in the treatment of light chain amyloidosis.

After many years, the management of systemic light chain (AL) amyloidosis is entering the era of evidence-based medicine, with three recently published randomized clinical trials, a regimen (daratumumab, cyclophosphamide, bortezomib, and dexamethasone, daratumumab-CyBorD) labeled for upfront therapy, more clinical trials ongoing, and published guidelines. In this review, we discuss how current practice is changing based on this data. Daratumumab-CyBorD grants unprecedentedly high rates of hematologic and organ response and became the novel standard-of-care in AL amyloidosis. The International Society of Amyloidosis and the European Hematology Association issued common guidelines for autologous stem cell transplant (ASCT) in this disease. Improved patient selection and effective induction regimens greatly reduced ASCT-related mortality. Venetoclax is emerging as a very effective option in patients harboring the common t(11;14) abnormality. Rapid and profound reduction of the amyloid free light chain can improve survival also at advanced stages. Daratumumab-CyBorD is being integrated into the treatment flow-chart whereas the role of ASCT is being redefined. New approaches are being tested in clinical trials. Treatment of daratumumab-refractory patients and validation of criteria of hematologic progression to be used in clinical trials and in individual patient management are current areas of research.

Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: Are we there yet?

Indolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms. In a small number of patients, hematologic progression is seen in the follow-up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, and neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MCs in ISM. Because MCs in more than 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The 2 such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even noneffective against KIT D816V and are thus recommended for use only in patients with other KIT mutant forms (noncodon 816 mutations) or with wild-type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat patients with ISM should be balanced against their toxicity and short- and long-term safety.