Treatment-related Mortality Research Articles

Evaluating Concordance between International Myeloma Working Group (IMWG) and Simplified Frailty Index (SFI) Among Older Adults with Multiple Myeloma (MM)

Introduction: Despite significant advances in therapeutics, older adults with MM are at increased risk of treatment related toxicity and mortality. Frailty is an aging-associated state of cumulative decline in many physiological systems, resulting in diminished resistance to stressors, including cancer therapy. In 2015, the International Myeloma Working Group (IMWG) developed a geriatric assessment (GA) based frailty index (IMWG-FI) using age, comorbidities, and physical function (instrumental activities of daily living, IADL; activities of daily living, ADL) to predict risk of toxicity and mortality among older adults with MM (Palumbo, et al., Blood 2015). However, GA is not routinely incorporated in clinical practice and a simplified frailty index (SFI; Facon et al Leukemia 2020) has been proposed as an alternative to using ECOG performance status (ECOG PS) as a proxy for physical function (IADL/ADL). However, the concordance between IMWG-FI and SFI remains relatively unknown, as well as their predictive ability in clinical practice, particularly among patients with relapsed, refractory multiple myeloma (RR-MM). Our goal was to describe the prevalence of frailty using IMWG-FI and SFI as well as evaluate their concordance among patients with newly-diagnosed (ND) and RR-MM. Methods: The Cancer and Aging Resilience Evaluation in Hematologic Malignancies (CARE-Heme) Registry is an ongoing prospective registry enrolling adults ≥50 years of age with a diagnosis of a hematologic malignancy undergoing treatment at a single institution. For this analysis, we included patients ≥50yo with ND- or RR-MM initiating a new treatment regimen (ranging from first to sixth line of treatment). All of the patients included in this study underwent a comprehensive GA prior to beginning a new line of therapy or stem cell transplant. We abstracted physician reported ECOG PS and comorbidities by reviewing medical records. We calculated IMWG frailty score as well as SFI using published methods. Each patient was categorized into frail/non-frail using the IMWG frailty score (fit, intermediate-fit, frail; collapsing fit/intermediate fit into the non-frail category) and the simplified frailty score (non-frail, frail) using published cutoffs. We measured the agreement between the total frailty scores using Spearman Correlation Coefficient and the frail/non-frail categorization using the Kappa statistic. Relevant treatment outcomes including progression-free survival, overall survival, and grade 2-5 toxicities (both hematologic and non-hematologic) were recorded until disease progression, death, or 6 cycles of treatment were completed. Results: A total of 146 adults with MM (49 ND-MM, 51 pre-transplant, and 46 RR-MM) starting a new line of therapy or ASCT between 8/2020 to 1/2022 were included in this study. The median age was 62 (IQR 57-70) with 53% males and 36% blacks. Most patients had IgG isotype (64%) with International Staging System (ISS) stage III disease (38%) whereas 30% patients had high risk cytogenetics. The distribution by IWMG Frailty category was as follows: 43% fit, 32% intermediate-fit, and 25% frail. Using SFI, 32% of patients were characterized as frail and 68% were characterized as non-frail (Figure 1). Although, the frailty scores were well correlated with each other (Spearman rho 0.67, p value <.001), the agreement between SFI and IMWG-FI in terms of frailty categorization was moderate (Kappa statistic 0.50); 79% of patients were classified in the same frailty group, however about 21% of patients were characterized in different frailty categories using the two scales (Table 1). SFI over-estimated frailty in about 14% of patients. There was very little agreement between a patient-reported vs physician rated ECOG-PS (Kappa statistic 0.13). The discordance between the two FI worsened if a patient reported version of ECOG PS (Kappa statistic 0.30) was used. Conclusions: Among older adults with MM, the prevalence of frailty ranged 25% by IMWG-FI to 32% by SFI. There was only a modest agreement between SFI and IMWG FI, which was worse when using patient reported version of ECOG PS. Studies comparing outcomes across the two frailty indices should take into account the potential for misclassification bias. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TP53 and Complex Karyotype Represent a Very High-Risk Group in Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation: An International Collaborative Analysis

BackgroundTP53 mutations (TP53MT) have been associated with poor outcomes in various hematologic malignancies, but no data exist on its role in patients with myelofibrosis undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Although HSCT remains the only curative treatment for myelofibrosis and its numbers continue to increase worldwide, its inherent treatment-related morbidity and mortality make adequate patients counseling crucial. Here, we took advantage of a large international multicenter cohort to evaluate the role of TP53MT in this setting. Patients and Methods Clinical data on myelofibrosis patients undergone first HSCT in 7 US and European centers, with detailed information on cytogenetics and NGS-based TP53MT at the time of transplant were collected. Results Among 349 included patients, 49 (13%) had detectable TP53MT, of whom 16 showing a multi-hit configuration. Median variant allele frequency (VAF) was 20.3% (range, 2.9-97.6%). No difference in age at HSCT was noted in TP53MT carriers as compared to wild type cases (median 56 vs 57 years, respectively). Cytogenetic risk (Tefferi et al. 2018) was favorable (n=248, 71%), unfavorable (n=79, 23%), and very high (n=22, 6%) with complex karyotype present in 36 patients (10%). Accordingly, when compared to wild type cases TP53MT carriers were enriched in the unfavorable cytogenetic risk category (20% vs 39%, P=0.01) and, importantly, in patients with complex karyotype (7% vs 29%; P<0.001). No significant difference was observed between both groups when accounting for ontogenesis of myelofibrosis (primary vs secondary), blood counts, constitutional symptoms, nontransplant (DIPSS) and transplant-specific risk stratification (MTSS), co-occurring mutations such as driver mutations (JAK2, CALR, MPL), high-risk mutations (ASXL1, SRSF2, IDH1/2, EZH2) and mutational burden. With a median follow-up from HSCT of 5.8 years for the TP53MT and 9.2 years for the non- TP53MT group, the 6-year OS achieved 35% vs 64%, respectively (P<0.001). As a result, median OS was 1.5 years (95% confidence interval [CI], 0.3-2.8 years) for the TP53MT vs 13.5 years (95% CI, 9.2-17.8) for the wild-type group. When stratified according to TP53 status and clonal burden (VAF), 6-year OS was 45% for monoallelic vs 24% for multi-hit TP53MT carriers (P=0.25), and 46% vs 27% for VAF <20% and VAF >20%, respectively (P=0.21). Current cytogenetic risk stratification showed no discrete survival differences (P=0.59), whereas complex karyotype still impacted on post-HSCT outcomes, with a median OS of 1.9 years (95% CI, 0-4.2) in such setting vs 13.5 years in cases with other karyotypes (P<0.001). Of note, interaction test for TP53MT and complex karyotype was not significant (P=0.25). TP53MTcarriers showed also significantly higher 6-year cumulative incidence of relapse (35% [95% CI, 21-49%] vs 17% [95% CI, 13-21%]; P=0.001) when compared to the non-TP53MT group. A total of 19 TP53MT patients (39%) experienced post-HSCT relapse with 10 (20%) presenting as leukemic transformation vs only 7 (2%) in the non-TP53 group. Importantly, nor the rate nor the time to leukemic transformation differed according to the TP53MT type. Furthermore, nonrelapse mortality was not significantly different between the TP53MTand wild-type group (P=0.22). In terms of cytogenetics, again the current risk stratification failed to separate patients with different relapse risks (P=0.73), whereas 6-year cumulative incidence of relapse achieved 31% in cases harboring complex karyotype as compared to 19% in patients with other cytogenetic configurations (P=0.03). When adjusting in 2 models either for MTSS or DIPSS, TP53MTand complex karyotype were independently associated with worse OS, showing HR of 1.76 (95% CI, 1.14-2.74) or 2.10 (95% CI, 1.34-3.31) and 1.64 (95% CI, 1.00-2.66) or 1.84 (95% CI, 1.10-3.08), respectively. While MTSS maintained its significant power (P<0.001), DIPSS was not significantly associated with OS (P=0.70). In terms of relapse, TP53MT, complex karyotype, circulating blasts and increasing MTSS scores independently associated with post-HSCT outcomes. ConclusionTP53 and complex karyotype represent a very high-risk group in myelofibrosis undergoing HSCT, informing prognostication for OS. Importantly, these features may also facilitate patient counseling regarding relapse after HSCT, together with current transplant-specific tools.

Treatment-Related Circulatory Diseases and Mortality in Hodgkin Lymphoma Patients Using Multi-State Modelling and Relative Survival

Introduction Diseases of the circulatory system (DCS) are some of the most common late effects of Hodgkin lymphoma (HL), primarily due to mediastinal radiotherapy and/or anthracycline-containing chemotherapy (e.g., ABVD and BEACOPP). As DCS is very common in the general population, modelling DCS attributable to HL therapy versus that expected in the general population is relevant to understand the magnitude of DCS reduction that could be achieved with less cardiotoxic therapies. This real-world data study used multi-state modelling and relative survival to estimate treatment-related DCS risk in HL survivors. Material and methods All HL patients registered in the Swedish Lymphoma Register 2000-2018, aged 18-80 years at diagnosis, and treated with anthracycline-containing therapy were included. DCS events were identified in the Swedish National Inpatient Register (ICD-10 codes I00-I99) and defined as the first admission for DCS after HL diagnosis. Sex-, year-, and age-specific DCS incidence rates in the general population were retrieved from public records. Patients were followed from treatment initiation through a series of states: alive and DCS-free, alive and with (excess or expected) DCS, dead without DCS, and dead after DCS. Follow-up ended on date of death, emigration, or December 31st, 2019, whichever came first. All state transitions were modelled separately using flexible parametric survival models, yielding hazard ratios (HR) with 95% confidence intervals (CI). A relative survival model incorporating the expected DCS rates was fitted to allow for estimation of excess DCS, which was then interpreted as treatment-related. Transition probabilities (i.e., the likelihood of being in a state) were predicted for specific patient groups, by sex and low/high (≤200/>200 mg/m2) cumulative anthracycline dose. Results In a total of 1,929 HL patients, the mean age at diagnosis was 42 years, 54% were males, and 49% were treated with high dose anthracycline (Table 1). The distribution of treatments was 66% ABVD, 20% CHOP-like, and 14% BEACOPP. During a median follow-up of 7.6 years (IQR: 4.5-11.0), 145 (7.5%) died without DCS, 377 patients (20%) were diagnosed with DCS, and 87 (5%) died after DCS. Figure 1a shows the sex-specific transition probabilities for a patient with advanced stage disease, diagnosed in 2000, at age 50, and treated with a cumulative anthracycline dose of >200mg/m2 in a ABVD regimen. The probability of being in the treatment-related (excess) DCS state at 10 years after first line treatment was 0.35 (95% CI: 0.09-0.75) for males and 0.41 (95% CI: 0.10-0.81) for females in this patient group. Figure 1b shows the probabilities for limited stage male patients diagnosed in 2000 at age 50, treated with ABVD, by low/high anthracycline dose. Here, the probability of being in the treatment-related (excess) DCS state at 10 years was 0.44 (95% CI: 0.16-0.76) and 0.53 (95% CI: 0.25-0.80) for low and high dose anthracycline patients, respectively. There were no significant differences in treatment-related (excess) DCS incidence rates or post DCS all-cause mortality rates (Table 1). Females had a significantly lower non-DCS mortality rate than males (adj. HR=0.69, 95% CI: 0.49-0.97), as did patients treated with high compared to low anthracycline dose (adj. HR=0.28, 95% CI: 0.18-0.44). Conclusion After 10 years, females had higher risks of treatment-related (excess) DCS compared to males, although not statistically significant and likely due to superior survival. The same was seen for high compared to low cumulative doses of anthracycline. Female sex and high dose anthracycline reduced the non-DCS mortality rate, but not the excess DCS incidence rate. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Stem Cell-Derived Gene Expression Scores Predict Survival and Leukemic Transformation in Myelofibrosis

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with survival outcomes ranging from months to years and variable risk of transformation to acute myeloid leukemia. Allogeneic bone marrow transplantation (BMT) can be curative but is associated with high treatment-related morbidity and mortality, therefore accurate risk stratification is important to guide clinical decision making in MF. Current risk prediction models use clinical and/or genomic features but do not consider the properties of the disease-driving stem cell population. Here, we use transcriptomic variation corresponding to both intra- and inter-patient heterogeneity among MF stem cells to generate novel gene expression-based scores predictive of survival and leukemic transformation in MF. To train and validate novel prognostic scores in MF, we identified 358 patients from an MPN registry at the Princess Margaret Cancer Centre (ClinicalTrials.gov Identifier: NCT02760238) from whom peripheral blood (PB) cells were collected near the date of MF diagnosis. All patients were diagnosed with either primary, post-PV, post-ET or pre-fibrotic MF with clinical follow-up of up to 12.2 years. RNA was extracted from unsorted PB mononuclear cells and RNA sequencing (RNAseq) was performed at an average depth of 50 million reads per sample. We randomly split our MF cohort into training (70%; n=250) and test sets (30%; n=108) and utilized a repeated nested cross validation approach together with statistical regression, to generate and assess the performance of models to predict survival within the training set. We tested 36,000 models derived from 36 initial MF-related genesets, ranging from stem-cell specific genesets to the whole transcriptome. The most accurate models by cross validation (median multivariable p-value = 6e-5) were produced from our retrospective identification of highly variable genes in single-cell RNAseq data derived from 82,255 Lin-CD34+ MF stem and progenitor cells across 15 patients (Psaila et al., 2020). Thus, features of intra- and inter-patient heterogeneity among MF stem and progenitor cells proved to be the most relevant for predicting survival. From these features, we derived our final model calculated as the weighted sum of gene expression across 24 genes (termed MPN24). We categorized patients with MPN24 scores above or below the training cohort median as MPN24 high or low, respectively. This model was validated in the test set, with high and low score patients experiencing 5-year survival rates of 71% [95% CI 57-88%] and 21% [95% CI 9%-52%], respectively, when censored at time of BMT (HR = 5.3 [95% CI 2.6-10.5]; p=2.1e-6) (Figure 1A). MPN24 retained independent prognostic value in multivariable analysis incorporating age, sex, DIPSS category, ECOG status, fibrosis grade, constitutional symptoms, and PB blast percentage (adjusted HR = 5.7 [95% CI 2.2-14]; p = 3e-4). Importantly, DIPSS classification remained a significant covariate, indicating that MPN24 and DIPSS capture distinct features of disease. We therefore developed a new three-tier classification scheme integrating both DIPSS and MPN24 scores (Figure 1B). Patients classified as low-, intermediate- or high-risk in this new classification scheme experienced 5-year survival rates of 88.2% [95% CI 77.9% - 99.9%], 39.3% [95% CI 19.9% - 77.7%] and 10.8% [95% CI 2.1% - 55.8%], respectively (likelihood ratio test p = 1e-8). Finally, from the MPN24 genes we derived a 13 gene subscore (MPN13) predictive of leukemic transformation in the training set. Patients in the test set scoring above the 80th percentile from the training set were classified as high risk and the remaining as low risk. Although total leukemic samples were limiting, MPN13 was significantly associated with risk of transformation (p=4.7e-03) with low and high-risk patients experiencing 3-year cumulative incidences of transformation of 5.2% [95% CI 0.2%-10.2%] and 28.6% [95% CI 3.1%-54.0%] respectively, after adjusting for death as a competing risk. Future studies will transfer our scores to the Nanostring platform for testing in independent cohorts. In summary, we used transcriptional variation among MF stem and progenitor cells to derive novel gene expression scores predictive of survival and leukemic transformation and developed a new integrated 3-tier model for predicting risk in MF patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Low Intensity Salvage Therapy after Failure of Standard (7 +3) Induction Regimen in Acute Myeloid Leukemia (AML). a Single Center Experience from United Arab Emirates

Hypomethylating agent (HMA) and venetoclaxR as salvage therapy for Acute Myeloid Leukemia (AML) failing intensive induction therapy. A single center experience from United Arab Emirates. Introduction: Patients with AML who are younger and fit for therapy are treated with intensive chemotherapy. Complete remissions (CRs) range from 40-80% (Kantarjian, Blood vol. 116,22 (2010): 4422-9). Non-CR patients can be treated with salvage therapy as a bridge to Allogeneic hematopoietic cell transplant (AlloHCT). Salvage regimens have included high dose cytarabine based therapies (FLAG, MEC, HAM) which can be more toxic limiting the use of AlloHCT. Lower intensity and more targeted therapy could decrease toxicity with improved responses. We describe our experience with a low intensity regimen as salvage treatment after failure of intensive induction therapy and bridge to AlloHCT. Methods: This is a retrospective analysis of AML patients treated at Tawam Hospital, UAE from 01/2019 to 06/2022. Patient data was collected from the medical records including: demographics, hemogram at presentation, bone marrow biopsies, karyotyping, treatment and response. Results: Eighty patients were diagnosed with AML during this period. The median age was 45 years (range 16-95 years). Fifty-seven patients received therapy while twenty-three patients refused or were not eligible due to comorbidities and / or performance status. Intensive chemotherapy (infusional cytarabine and idarubicin 7+3 or FLAG) was used for thirty-three patients. The median age was 35 years (range 16 - 63 years). Cytogenetics (Metaphase Karyotyping and FISH): normal, n=7; good risk n=6 (inv 16 or t (8;21), growth failure n=5, poor risk n=10 (Complex = 3, Del 7 = 3, 11q abnormalities = 3, trans 6;9 =1) other n=5. Molecular testing for NPMI, FLT3, IDH1 and IDH2 was not available. Three patients died during induction and are excluded from analysis. Fifteen patients attained CR after 1 cycle of induction (50%). Twelve patients not in CR received outpatient, low intensity salvage therapy with HMA (5 azacitidine 75 mg/m2 daily x 7 days subcutaneously with Venetoclax 100 mg orally daily x 21 days along with antimicrobial prophylaxis with azoles in 28 days cycles). Bone marrow was repeated after the second cycle. The median number of cycles is 3 (range 1-9). Eight (67 %) achieved CR1. There were no treatment related deaths. This is comparable to our report of FLAG salvage therapy (Hassan IB. Int J Hematol. 2018 Oct;108(4):390-401). Four of the eight patients who achieved remission went for AlloHCT while one is awaiting AlloHCT. One patient is unable to go for HCT and is in remission after 9 cycles of therapy. Two patients after achieving CR relapsed and died of disease progression. With a median follow up of 123 days (range 33 -1107 days) five patients are alive and in remission, one has been lost to follow-up while the other six have died from progressive disease and complications. Conclusion. Low Intensity therapy with HMA and Venetoclax is a reasonable and effective alternative to intensive chemotherapy as first line salvage with minimal morbidity and zero treatment related mortality. Treatment was well tolerated and no patients required hospitalization for complications. This regimen is easily administered as an outpatient, serving as a bridge to AlloHCT

Not Yet Time to Retire Splenectomy in Splenic Marginal Zone Lymphoma (SMZL): Results of a Single Center Experience

Introduction The SMZL is a rare and indolent disorder that mainly affects elderly and middle-aged patients (pts). Therapy is indicated for constitutional symptoms, massive splenomegaly, or cytopenia and about one third of pts will never require therapy. In the past two decades, splenectomy has been progressively replaced by Rituximab (RIT)-based treatments (with or without chemotherapy) as the first line therapy in symptomatic SMZL. Long-term disease control is obtained in about 50% of pts with RIT alone and in 68% with chemotherapy-RIT combination, without significant difference in term of overall survival (OS) with the two approaches. However, RIT monotherapy is not allowed in several Countries, including Italy. Furthermore, in the COVID-19 era, treatment with anti-CD20 showed a negative impact on the clinical outcome of infected pts, by limiting its recommendation. In 2017 we published the experience of our Center in splenectomy as a front-line treatment of SMZL (Pata et al. Int Journal of Surgery 41, 2017), highlighting the feasibility and the few, acceptable adverse events related to the procedure. We also reported a comparative analysis between pts who underwent splenectomy as the only first line approach and pts who were treated with systemic therapy (Pagani et al. Haemat 2015; 100 s3). Here, we report long term results to verify the effectiveness of splenectomy as a first-line therapy in SMZL and to identify predictors of progression and the need for re-treatment. Methods and patients The retrospective analysis included all pts consecutively diagnosed and treated for SMZL at our Institution aged >18 years. Indications for treatment were symptoms related to splenomegaly or cytopenia due to hypersplenism. The choice of treatment was based on physician decision. All pts who underwent splenectomy were vaccinated for encapsulated bacteria (Pneumococcus, Hemophilus Influenza B, and Meningococcus ACWY). Response assessment was made as recommended by International Workshop criteria. Survival analysis was performed with Kaplan-Meier method and univariate analysis with Log-Rank test with a significance at 0.05. Results From May 1997 to November 2014, 91 SMZL pts were treated. Of these, 54 underwent splenectomy (cohort 1) and 37 received systemic therapy (cohort 2). Pts characteristics and treatment received are shown in Table 1. Only leukocyte count and bone marrow (BM) involvement at diagnosis significantly differ in the two cohorts. Overall response rate (ORR) was 91% in cohort 1, [5% complete remission (CR)] and 76% in cohort 2 (32% CR). Hematologic and nonhematologic side effects were acceptable and no treatment related mortality occurred in both groups, as already reported. After a median follow-up of 102 months (range 1-275) 56% and 54% of pts progressed in cohort 1 and 2 respectively, p not significant (p ns). Median time to next treatment (TTNT) was 77,3 months in cohort 1 and 128,1 months in cohort 2 (p ns), with 10-years (yrs) TTNT of 43% versus 58%, respectively. Histological transformation occurred in 18% of pts in cohort 1 and 8% in cohort 2 (p ns). The 10-yrs progression free survival (PFS) and OS were not significant different in cohort 1 and 2 (PFS 42% and 36% and OS 71% and 62%, respectively). In univariate analysis, within cohort 1, BM infiltration more or less than 30% had a significant impact on TTNT: median TTNT of 26,9 months with BM >30% versus not reached with BM <30%, with 10-yrs TTNT of 22% vs 53%, respectively (P 0.017). Figure 1. Conclusions With a long follow up, splenectomy is confirmed to be an effective alternative option to systemic treatment in SMZL. Moreover, in this pandemic period and especially in patient with low BM burden (infiltrate <30%), splenectomy should be considered as first line approach. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Feasibility and Improvement in Survival with a Risk-Adapted Treatment Regimen for Childhood Acute Lymphoblastic Leukemia in a Limited Resource Setting

Introduction: High-intensity therapeutic regimens results in ALL have not been reproduced in limited resource settings, due to the lack of appropriate support therapy, diagnostic methods, limited access to drugs, and high treatment related mortality. For low and middle-income countries, treatment of these patients represents a challenge. In Mexico acute leukemia represents 49% of all pediatric cancers, with a 5-year overall survival between 50 and 60%, a relapse rate of 26%, induction related mortality of 3-10%, and a mortality in remission of 14%. We report the results of an adjusted treatment regimen based on an adapted risk stratification for a limited-resource setting. Objective: To implement a risk stratified treatment protocol for a limited resource setting, with the aim of reducing induction related mortality, and improving EFS and OS. Materials and Methods: From January 2017 to March 2020, all patients diagnosed with ALL between 0 and 15 years of age in a single center in northeast México were captured in a prospectively maintained database. Depending on risk stratification, patients received an adjusted treatment protocol with variations on intensity and duration for the different phases. The main differences were the amount of anthracycline doses during induction (2 for low, 3 for intermediate/high patients), the requirement of at least 20 doses of L-asparaginase for intermediate/high risk patients, and the use of Capizzi-style methotrexate for intermediate risk and high-dose methotrexate only for high-risk patients (Table1). Demographic data was reported using distribution analysis, and the Kaplan-Meier method was used to analyze and predict OS and EFS. Results: There were 59 male and 41 female patients; the median age at diagnosis was 5.5 years. B-cell and T-cell lymphoblastic leukemia was the diagnosis in 94% and 6% patients, respectively, with a follow-up of 41 (0.33-65) months. Regarding risk stratification, 42%, 34%, and 24% children were classified as high, intermediate, and low-risk, respectively. After one week of corticosteroids 80% of patients had a good response, and 84% of patients achieved a negative measurable residual disease (MRD) after induction chemotherapy. Estimated EFS and OS at 5 years were 70% and 77.5% respectively. Of the 93 patients evaluable for response, MRD positivity (16%), induction related mortality (6%), and relapse (16%) rates were lower in this cohort when contrasted with previous protocols. EFS for low, intermediate, and high-risk groups was 73%, 85%, and 56% and OS 88%, 90% and 61% (Figure 1) Conclusions: The implementation of a risk-adjusted chemotherapy regimen adapted for our limited-resource center, improved treatment continuity and was associated with better OS, and EFS. Early relapse rates were also reduced, without increasing induction mortality associated with toxicity. Periodic and prospective outcome evaluation in a limited-resource setting is fundamental to adjust and standardize therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Alternative Reduced Intensity Conditioning for Allogeneic Blood and Marrow Transplantation Using Pentostatin, Cyclophosphamide, and Total-Body Irradiation with Post-Transplant Cyclophosphamide

Reduced-intensity conditioning (RIC) regimens for allogeneic blood and marrow transplant (alloBMT) offer lower treatment-related mortality than myeloablative conditioning. Fludarabine is a key agent for the majority of RIC and nonmyeloablative regimens, including in combination with cyclophosphamide, total body irradiation (TBI), and post-transplant cyclophosphamide (PTCy). Critical supply chain shortages of fludarabine highlight the need for substitute regimens. Herein we report the use of a novel RIC approach utilizing pentostatin as an alternative purine antimetabolite in adults receiving alloBMT for hematologic malignancies. The RIC conditioning regimen included pentostatin 4 mg/m2 IV and cyclophosphamide 14.5 mg/kg IV on days -5 and -4 and TBI 400 cGy on day -1 (PentoCyTBI). Pentostatin was reduced by 50% for creatinine clearance < 50 mL/min. TBI 400 cGy was chosen over 200 cGy to maximize immunosuppression and engraftment. Graft-versus-host disease prophylaxis consisted of cyclophosphamide 50 mg/kg IV on days +3 and +4, mycophenolate mofetil beginning day +5 through day +35 and either tacrolimus or sirolimus beginning day +5 through day +60 to +180. Patients who were at least 28 days post-alloBMT were included in the engraftment analysis, while all patients who completed conditioning were included in the toxicity analysis. Neutrophil engraftment was defined as an ANC ≥ 0.5 × 109/L measured for three consecutive days and platelet engraftment was defined as a platelet count ≥ 20 × 109/L for three consecutive days without platelet transfusion in the preceding seven days. Between 06/2022 and 07/2022, 11 patients received PentoCyTBI at The Johns Hopkins Hospital. The median follow-up was 16 days for all patients (range 8-36). Patient characteristics are summarized in Table 1. The median age was 54 years (range 27-74), 55% were male, and 36% were ethnic minorities. The most common indication for transplant was acute myeloid leukemia, with 73% of patients receiving peripheral blood as the stem cell source, and 73% from haploidentical donors. Of 4 patients with Day +28 follow-up, all had neutrophil engraftment at median 17 days (range 12-19) and 3 had platelet engraftment at median 25 days (range 19-29) (Table 2). One patient was excluded from the platelet engraftment analysis as platelet transfusions were continued while on hemodialysis despite achieving a stable platelet count ≥ 20 × 109/L. Nausea and vomiting during conditioning and neutropenic fever were the most common acute toxicities occurring in 4 patients (36%) each, though 3 cases of neutropenic fever were attributed to cytokine release syndrome. There were no reports of grade ≥ 3 hepatotoxicity. One patient experienced nephrotoxicity beginning Day +8, escalating to grade 4 requiring hemodialysis; conditioning included pentostatin dose reduction for baseline renal impairment and it is uncertain whether pentostatin contributed. Options for alloBMT RIC without fludarabine are extremely limited. Early results using pentostatin as an alternate purine analog are encouraging, with full engraftment to date and similar timing to fludarabine-based regimens. Further patient volume and follow-up will be collected to assess long-term efficacy and safety outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Reduced Intensity Reinduction Followed By Blinatumomab Achieves Excellent MRD Clearance with Reduced Toxicity and Facilitates Timely Transplant in Children and Young People with Relapsed B-Precursor Acute Lymphoblastic Leukemia

Introduction Despite the emergence of effective novel immunotherapies, the outcome of relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains poor due to treatment-related mortality (TRM) and resistant disease. In response to accumulating evidence on the efficacy and low toxicity of blinatumomab in relapsed B-ALL and the availability of highly active CD19-targeted chimeric antigen receptor T-cell therapy (CART), we redesigned the United Kingdom (UK) relapse treatment pathway, based on two key guiding principles: 1) to reduce chemotherapy burden and associated toxicity through a move away from the highly intensive ALL R3 backbone towards increased reliance on blinatumomab to clear disease, and 2) to identify treatment failures early and direct them to CART, given the poor responses reported with hematopoietic stem cell transplant (HSCT) in this context. Methods Patients were treated with UKALL induction chemotherapy (<16yr: 3-drugs; >16yr: 4-drugs) until adequate blast clearance. Patients with blasts <5% at Day 15 progressed directly to blinatumomab; remaining patients continued to Day 28. Following reinduction, patients received up to 2 cycles of blinatumomab as a single agent. HR patients (early/very early relapses and/or HR cytogenetics) proceeded to HSCT once minimal residual disease (MRD) <0.01%. Those with high-risk (HR) isolated central nervous system (CNS) disease had the option to proceed directly to HSCT following CSF blast clearance without blinatumomab. All Standard risk (SR) patients continued on chemotherapy alone. Patients who were refractory after re-induction (>25% disease), blinatumomab (MRD >0.01%), or for whom there was no available donor were considered for CART. All patients were required to be discussed at a national tumour board, and data were subsequently collected every 3 months for analysis. Events were defined as death, relapse, and secondary cancer. Results Between September 2018 and July 2022, 111 patients were treated on the pathway; 63 (56.8%) were HR and 48 (43.2%) were SR. There were 26 patients >15yr, 3 Infant ALL, 2 Ph+ ALL and 4 with Down Syndrome. Induction therapy achieved disease reduction to <5% and CNS clearance in 98 patients (88%). Of the 90 patients with BM involvement, 52.2% required only 15 days of induction therapy. Induction failure (>25% blasts) occurred in 6.3%, comparable to the 7.1% using the R3 induction in the COG AALL1331 trial (p=1.00); 6/7 patients with induction failure successfully underwent CART infusion. The rate of end of induction MRD <0.01% in the HR group was also similar to COG AALL1331 (30% vs. 27.4%, p=0.669). Importantly, there were no cases of TRM with the reduced intensity induction, compared to 2.4-4% reported with the ALL R3 induction (p=0.06). Ninety patients received blinatumomab, of whom 87% achieved a complete MRD response, with grade 3 or 4 treatment-related toxicity in 11 patients (12.2%). Amongst HR patients, 86.8% underwent HSCT, significantly more than in the blinatumomab-treated IR/HR arm of COG AALL1331 (66%, p=0.02). With a median follow-up of 12 months (range 2-49), 19% of HR patients and 8.3% of SR patients have relapsed, comparable to results achieved in the blinatumomab-treated arm of the COG AALL1331 trial. There were no deaths in the SR group, and 12 deaths in the HR group (6 due to relapse/refractory disease, 6 due to post-HSCT TRM). Conclusions Our findings demonstrate that a reduced intensity reinduction can achieve equivalent disease control to the more intensive ALL R3 induction, with a substantial reduction in TRM. Although follow-up is short, consolidative blinatumomab achieved very high rates of MRD clearance, allowing a greater number of HR patients to reach potentially curative therapy with HSCT, the key predictor of outcome in the COG AALL1331 trial. We propose that our strategy represents a new standard of care for reinduction therapy in relapsed childhood B-ALL. DO and AV are joint senior authors Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Addition of Sorafenib to Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone (CLAG-M) in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) and High-Grade Myeloid Neoplasms Independent of FLT3-Mutation Status: Final Results of a Phase 1/2 Study

BACKGROUND: We previously showed that cladribine, cytarabine, G-CSF and dose-escalated mitoxantrone (CLAG-M) led to a higher rate of complete remissions without measurable residual disease (MRDneg CR) than 7+3. Recently, a randomized trial demonstrated addition of the multikinase inhibitor sorafenib to 7+3 improved event free survival (EFS) irrespective of FLT3 mutation status. Here, we report the results of a phase 1/2 study (NCT02728050) evaluating addition of sorafenib to CLAG-M (CLAGM+S) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms (≥10% blasts). Phase 1 results were reported previously. METHODS: Patients aged 18-60 years were eligible if they had a treatment-related mortality score (TRM) of ≤13.1 (corresponding to a predicted <13.1% risk of death by day 28 following intensive induction chemotherapy) and adequate organ function. Patients with uncontrolled infection or concomitant illness with expected survival <1 year were excluded. Cohorts of 6-12 patients were assigned to 1 of 6 dose levels of mitoxantrone (10, 12, 15, or 18 mg/m2/day, days(d) 1-3) and sorafenib (200 to 400 mg twice daily [BID] on d10-20 with induction and 8-27 with consolidation). G-CSF dose was 300 or 480 μg/day (weight-based, d0-5), cladribine 5 mg/m2/day (d1-5), and cytarabine 2 g/m2/day (d1-5). Up to 4 cycles of post-remission therapy with CLAG+S (mitoxantrone omitted) were allowed, followed by 12 months of maintenance sorafenib. Patients were taken off trial if they underwent allogeneic transplant. As primary endpoint in Phase 2, the rate of MRDneg CR following CLAGM+S was compared to a matched historical control population who received CLAG-M alone. Secondary endpoints included rate of CR, overall response rate (ORR defined as CR+CR with incomplete hematologic recovery [CRi]), overall survival (OS), EFS and the toxicity profile. EFS and OS were estimated using the Kaplan-Meier method and compared using Cox regression models. RESULTS: 84 patients were enrolled from 12/8/2016-10/7/2021. In Phase 1, CLAG-M with mitoxantrone at 18 mg/m2/day and sorafenib 400 mg BID was established as the recommended phase 2 dose (RP2D). Sixty-one patients with a median age of 50 [range: 21-60] years were treated at the RP2D. ELN2017 risk category was favorable in 28%, intermediate in 36%, and adverse in 34%. FLT3-ITD and TKD mutations were present in 28% and 7% respectively. Mortality within 28 days was 2%. At the RP2D, a response of MRDneg CR occurred in 49/61 patients (80%, 95% CI: 68-89%). Additional responses of MRDpos CR and CRi (3 patients each) led to an ORR of 90%. The MRDneg CR rate in patients with and without FLT3-mutations was similar (90% vs. 83%, p=0.30). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 29 and 25 days. Besides infections/neutropenic fever, rash was the most common grade ≥3 adverse event. With a median follow up of 35 months, median OS was not reached; 12-month OS was 82%. There was no difference in OS and EFS in the FLT3-mutated and FLT3-wild type patients. We next compared CLAGM-S to a historical cohort of 71 newly diagnosed patients treated with CLAG-M alone, matched for mitoxantrone dose, age and TRM score (Table 1). In univariate analysis, rates of MRDneg CR, OS and EFS were similar (p=0.83, 0.16, and 0.37 respectively). Likewise, there was no difference in OS (p=0.54) or EFS (p=0.63) in FLT3-mutated patients who received CLAGM+S vs CLAG-M. In subgroup analysis, we observed a benefit favoring CLAGM+S for both OS (p<0.01) and EFS (p=0.03) among ELN2017 intermediate risk patients (Figure 1). No benefit of CLAGM+S vs CLAG-M alone in either OS or EFS was observed among adverse risk patients. Analysis of the favorable-risk cohort was limited by small sample size. Multivariate models comparing CLAGM-S to CLAG-M alone (reference) and controlling for age, secondary disease, FLT3 status and cytogenetic risk showed improved OS (HR=0.38, 95%CI 0.17-0.84, p= 0.02) and EFS (HR= 0.43, 95% CI 0.22-0.85 p=0.02) following CLAGM-S; MRDneg CR was also more likely with CLAGM-S though not statistically significant (OR= 2.56, 95% CI 0.68-9.61, p= 0.16). CONCLUSION: Addition of sorafenib to CLAG-M produces high rates of MRDneg CR in newly diagnosed AML patients ≤60 and prolongs OS and EFS in multivariate analysis compared to historical, matched control cohort receiving GLAG-M alone, a benefit that was particularly evident in patients with intermediate-risk disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Outcomes for Acute Promyelocytic Leukemia: Need to Address Induction Mortality

Treatment outcomes of acute promyelocytic leukemia (APL) show variation between clinical trials and real-world setting largely due to exclusion of patients who present with major bleeding, severe infections and those who die within the first week. Use of differentiation agent-based therapy for low/intermediate risk group (ATRA and ATO) and limiting anthracycline use to high-risk subgroup has reduced the treatment-related mortality beyond first week. However, use of steroids for treatment of differentiation syndrome and chemotherapy can still increase the risk of infections which can compromise the outcomes, particularly in a setting with high incidence of multi-drug resistant organism and invasive fungal infections. There is a need to identify the predictors of this mortality and ways to reduce it to improve the outcomes. We analyzed the data for patients with newly diagnosed APL from two large tertiary care centers in India, registered between 2013-2018to evaluate the outcomes in all risk groups (as per Sanz score), mortality within first 30-days and prognostic factors. Patients with low/intermediate risk were treated with ATRA and ATO based therapy whereas the high-risk group received chemotherapy in addition to ATRA/ATO. We recorded demographic variables, white blood cell count and platelet count at diagnosis, Sanz score, serum albumin, serum creatinine, treatment administered, achievement of morphological complete remission post induction and complete molecular remission post consolidation, relapse and death. The primary outcome was event-free survival (EFS) which counted lack of complete remission post induction, lack of complete molecular remission post consolidation, relapse and death as event. The secondary outcomes were relapse-free survival (RFS), overall survival (OS) and induction mortality (death within first 30 days) and assessment of impact of baseline disease and host factors on the EFS, RFS, OS and induction mortality. A total of 238 patients were included in this analysis. The median age was 34 years (range 2-72 years) with male: female ratio of 1.5:1. At presentation the median WBC count was 6790 per cumm (range 300-237,000per cumm) and median platelet counts were 21000 per cumm (3000-266,000 per cumm). As per Sanz score - 12% were low-risk, 48% were intermediate risk and 40% were high-risk. Median fibrinogen levels were 239 (range 36-883). A total of 231 patients received therapy. A total of 204 patients were assessed for response at the end of induction and all but one patient achieved complete response (87.8% as per intention to treat). The rest were not assessable due to death during induction (19) and loss to follow up (15). The induction mortality was 8.2% (infections-6, coagulopathy-9, differentiation syndrome-2 and others-2).170/185(92%) patients achieved post consolidation complete molecular remission. A total of 19 patients relapsed during the follow up (bone marrow-14, CNS alone-2 and combined -3). The median time to relapse was 23.9 months (IQR 13.6-42.9 months). At a median follow up of 51.2 months,3-year EFS, RFS and OS were 79%,92% and 88%. There was no statistically significant difference between low, intermediate and high-risk group for any of the survival outcomes. Similarly, age, gender, fibrinogen and albumin at diagnosis did not have any adverse impact. Baseline WBC of >40000/cumm and serum creatinine of >2 mg/dL at diagnosis adversely affected the overall survival with HR of 3.22 (95% CI 1.42-7.29, p-0.005) and 11.9 (95% CI-2.78-50.82)respectively. However, the number of patients with raised creatinine were very small (n=4). These two factors had adverse impact on induction mortality too (WBC>40,000 per cumm - HR -3.32, 95% CI-1.31-8.42, p-0.012 serum creatinine >2 mg/dL- HR 14.69, 95% CI-3.36-64.18, p<0.0001). The survival probabilities at 3, 4 and 5 years using 30-day landmark analysis were 96%, indicating that there are very few deaths after the first 30 days of induction. Fig 1 depicts the overall survival. This retrospective analysis highlights that ATO+ATRA and minimal anthracycline based therapy has led to similar outcomes in all risk groups and the present need to address induction mortality. High induction mortality in patients with WBC >40,000/cum indicates the potential contribution of infections due to use of steroids to treat differentiation and underlying coagulopathy or a different biology. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax, Cladribine Plus Low-Dose Cytarabine Achieved High Remission in Patients with Relapse/Refractory Acute Leukemia: Preliminary Results of a Phase II Study

Background: Patients with relapse/refractory acute leukemia often show resistance to conventional chemotherapy and have dismal prognosis. Salvage therapy using venetoclax combined with hypomethylating agents achieved an overall response rate of approximately 40% in relapsed/refractory (R/R) acute myeloid leukemia (AML) patients. Cladribine is an adenosine deaminase resistant analog of adenosine. The efficacy of cladribine and venetoclax in R/R acute leukemia (AL) has not been reported. Here, we report preliminary results of venetoclax, cladribine plus low-dose cytarabine (CAV regimen) in the treatment of R/R AL. This study was registered at ClinicalTrials.gov (NCT05190549). Methods: 30 patients were enrolled from March 2021 to May 2022 at the First Affiliated Hospital of Soochow University. 21 patients were diagnosed with R/R AML (6 patients with favorable risk, 2 patients of intermediate risk and 13 patients with high risk at diagnosis) (Table 1). Seven patients were diagnosed with R/R Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (ALL) (5 with high risk and 4 patients of unknown). The CAV regimen consisted of cladribine 5 mg/m2/day from day 1 to day 3 or day 5, cytarabine 20mg/m2, q12h for 7-10 days, venetoclax 100mg d1, 200 d2, 400 mg/day from day 3 to day 28 (The exact number of days is at the investigator's decision). Bone marrow evaluation were performed within 1 week at the end of treatment. Results: The median age of enrolled patients were 39 in AML and 35 in ALL. 13/21 (66.9%) of AML patients and 5/9 (51.6%) of ALL patients had high-risk cytogenetics at diagnosis. All patients showed early relapse (less than 12-months from CR1). After one cycle of the CAV regimen, the overall response rate (ORR=CR+CRi+MLFS+PR) for AML was 90.5%. The rate of CR/CRi/MLFS was 81% in AML and CR/CRi was 55.6% in ALL. The estimated 1-year overall survival (OS) in AML and ALL was 91.7% and 100%, respectively. The event-free survival (EFS) for AML and ALL were 74.9% and 87.5%, respectively. The median OS, EFS of one year for all 30 patients were not reached. There was no significant statistical difference of disease type in OS (P=0.162) and EFS (P=0.935). During the treatment with CAV regimen, 7 patients (33.3%) developed grade 1 to 2 elevated transaminases. 5 patients (23.8%) developed grade 1 to 2 nausea and vomiting and 1 patient(7.4%) developed grade 3 nausea and vomiting. 3 patients(14.3%) developed grade 1 to 2 skin pruritus and rash. During a median follow-up of 116-days, 3 patients died of disease relapse(Picture1,2). There was no CAV treatment-related mortality. Conclusion: The CAV regimen was an effective and safe salvage strategy in relapse/ refractory acute leukemia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chidamide Plus Prednisone, Cyclophosphamide, and Thalidomide (CPCT) for Relapsed or Refractory Peripheral T-Cell Lymphoma: A Multicenter Phase II Trial

Purpose: Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of aggressive lymphomas that portends an unfavorable outcome. Although the treatment of PTCL has undergone advancements during the past several years, the response rate and long-term effects with respect to patients with PTCL remain unsatisfactory-particularly for relapsed or refractory (R/R) patients. We herein conducted a prospective, single-arm phase II clinical trial to explore the efficacy and safety of an all-oral regimen of chidamide plus prednisone, cyclophosphamide, and thalidomide (CPCT) for R/R PTCL patients who could not tolerate standard chemotherapy for a variety of reasons. Methods: This was an open-label, single-arm, multicenter pivotal phase II study in which patients were enrolled at 9 centers. The flow chart of the CPCT regimen: a total of fewer than 12 cycles as an induction-combined treatment period, and then applied chidamide as single-drug maintenance. The CPCT regimen was administered orally until disease progression or unacceptable toxicity as follows: chidamide at 30 mg twice weekly, prednisone at 20 mg daily after breakfast, cyclophosphamide at 50 mg daily after lunch, and thalidomide at 100 mg daily at bedtime. Our primary objective was to assess overall response rate (ORR) after treatment with CPCT, with secondary objectives to evaluate the duration of response, one-year overall survival (OS), and one-year progression-free survival (PFS). Results: Forty-five patients were ultimately enrolled in the present study for response and safety assessments from August 2016 to April 2021 with respect to Chinese patients (the characteristics of the 45 patients with at least one treatment response assessment are listed in Figure 1A). Twenty-three patients (51.1%) were heavily pretreated before enrollment. Of the 45 enrolled patients, the optimal ORR and complete response (CR)/CR unconfirmed (CRu) were 71.1% and 28.9%, respectively, and after a median follow-up period of 56 months, the median PFS and OS were 8.5 and 17.2 months, respectively (Figure 1B). The median median duration of response (DOR) was six months with a range of 0.7-71.5 months, and most responders (41 patients, 91.1%) had a DOR more than three months. Twenty-eight patients (62.2%) exhibited a DOR over six months and 17 patients (37.8%) had a DOR over 12 months. The one-year PFS and OS rates were 42.2% (95% CI, 27.7%‒56.7%) and 57.8% (95% CI, 43.3%‒72.3%), respectively, and the five-year PFS and OS rates were 21.2% (95% CI, 7.9%‒34.5%) and 43.8% (95% CI, 28.3%‒59.3%), respectively. Although subgroup survival analysis indicated no significant differences among different histopathologies (Figure 1C and D), the median PFS (p<0.001) and OS (p<0.001) were not attained for patients who achieved CR/CRu (N=13) (Figure 1E and F). The most common grade 3/4 adverse event was neutropenia (24.5%), but we observed no treatment-related mortality. Conclusions: In conclusion, the all-oral CPCT regimen was a well-tolerated and effective treatment for R/R PTCL patients who could not tolerate standard chemotherapy for a variety of reasons. However, further studies that entail a larger sample size in different subtypes of PTCL are still required. This trial was registered in ClinicalTrials.gov (NCT02879526). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Overview of Acute Myeloid Leukemia in Adults at the Peruvian National Cancer Institute (INEN)

Introduction: Acute myeloid leukemia (AML) 5-year overall survival (OS) previously reported is 16%, which is half of the median 5y OS in the United States. Therefore, to understand this significant disparity we aim to explore the clinical characteristics of AML patients diagnosed and treated at the National Cancer Institute in Peru. Methods: We conducted a retrospective analysis of all newly diagnosed AML patients seen at the National Cancer Institute (INEN) in Lima-Peru between 2015 to 2020. We include patients between 18-60 years old who received induction therapy. Exclusion criteria were acute promyelocytic leukemia, and AML secondary to MDS. Demographic and clinical characteristics were obtained from medical records, and risk stratification was done following the new criteria of the European Leukemia Network 2022. Survival analysis was performed using Kaplan Meier in SPSS. Results: A total of 390 newly diagnosed AML cases met inclusion criteria. The median age at diagnosis was 46 years, and patients were 52.7% male and 47.3% female. According to French American British (FAB) classification, the most common form was M2 (50.9%) followed by M4 (22.8%), M1 (11.9%), M5 (8.7%), and M0 (5.1%). ENL 2022 risk stratification was favorable (22.6%), intermediate (47.1%), adverse (13.9%), and unknown (16.3%). After induction therapy, 32.6% had a complete response (<5% blast in BM), 26.2% partial response, 13.4% no response and 27.8% non-evaluable response. Minimal molecular disease (MRD) was negative in 80.1% (101) of patients who achieved complete response. Response to induction chemotherapy by risk stratification groups is described in Table 1. Median overall survival was 7.2 months [5.8-8.6], and median OS by risk group was 10.1 months for the favorable group, 6.9 and 7 months for the intermediate and adverse respectively (Figure 1). Early death, defined as 60 days from commencing therapy, was 37.3% of all death. During this period, thirty patients went under allogeneic transplant, the median OS was 28.12 months. Conclusion: AML is a lethal disease in Peru, even for patients who are candidates for intensive chemotherapy, overall survival in this young cohort was dismal compared with reported international outcomes. A third of the deaths are within 60 days of starting the induction, which is related to treatment-related mortality and more studies are needed to narrow this outcome. In this Hispanic cohort, the favorable risk group has better outcomes, as expected, but intermediate and adverse groups have no difference in overall survival or response rates, suggesting intrinsic factors are associated and more cytogenetics and molecular studies are needed in Peruvian population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Newly Diagnosed Therapy-Related AML and AML with Myelodysplasia-Related Changes Treated with 7+3, Hypomethylating Agents with or without Venetoclax and CPX-351: A Retrospective Cohort Study

Introduction Therapy-related acute myeloid leukemia (t-AML) and AML with myelodysplasia-related changes (AML-MRC) are associated with poor outcomes due to older age at diagnosis and adverse-risk cytogenetics and molecular features and, therefore, treatment of these groups of patients remain a challenge. There is a paucity of real-world data on outcomes of t-AML and AML-MRC treated with 7+3, hypomethylating agents (HMA) with or without venetoclax (VEN) or CPX-351 (Vyxeos). Methods We conducted a single-center retrospective cohort study to compare overall survival (OS), event-free survival (EFS), and composite complete response (CCR) of patients with t-AML or AML-MRC treated with first-line 7+3, HMA, HMA+VEN or Vyxeos. Therapy-related myelodysplastic syndrome were not included. OS was defined from day 1 of initial chemotherapy until death from any cause. Patients were not censored at the time of allogeneic transplant. Sixty and 90-day treatment-related mortality were estimated as surrogates for treatment toxicity. Propensity score modeling was used to adjust for baseline characteristics (age, AML subtype, comorbidities, performance status, cardiac ejection fraction, cytogenetics, and mutations). Results Of 488 consecutive AML patients treated at the University of Maryland between 2013-2021, 136 patients had t-AML or AML-MRC and received one of the above therapies. 40% were female. The median age of the cohort was 67.5 [IQR: 60.9-73.2]. The median age of patients who received 7+3 (n=34) was 63.4 years, HMA (n=61) 70.3 years, HMA+VEN (n=27) 72.6 years, and Vyxeos (n=14) 62.2 years (age P-value= 0.1). 42 and 17 patients received decitabine in the HMA and HMA+VEN arms, respectively. None of the patients treated with 7+3 or Vyxeos received HMA prior to AML diagnosis. However, 3 and 6 patients received HMA in the HMA and HMA+VEN arms prior to AML diagnosis, respectively. Both 7+3 and HMA were given mostly before 2019 (7+3: 88%; HMA: 81%) compared to HMA+VEN and Vyxeos, which were given mostly in years 2019 and after (HMA+VEN: 74%; Vyxeos: 71%) (P<0.01). The median follow-up was 73.5 months (mo). Table 1 demonstrates unadjusted outcomes. Figure 1 demonstrates the unadjusted OS of treated groups. Using propensity score for adjustment, there was no difference in median OS or CCR in patients treated with 7+3 vs. HMA (11.2 vs. 10.6 mo, P=0.63; 42% vs. 31%, P=0.38). However, patients treated with HMA+VEN had worse adjusted m-OS than patients treated with 7+3 (5.3 vs. 20.2 mo, P=0.02) or HMA alone (5.3 vs. 10.1 mo, P=0.02). Patients treated with Vyxeos had a statistically similar adjusted-median OS to those treated with 7+3 (5.1 vs. 15.4 mo, P=0.34) and a trend toward a worse outcome than those treated with HMA alone (5.3 vs. 10.1 mo, P=0.07). Conclusion The outcomes of t-AML and AML-MRC remains poor. In t-AML and AML-MRC, using 7+3 and HMA resulted in similar OS; however, improved outcomes compared to HMA+VEN. Almost 50% of patients treated with HMA+VEN died in the first 90 days, possibly related to treatment toxicity. Further studies are needed to determine the role of VEN combination with HMA in t-AML and AML-MRC. Moreover, further real-world, multi-institutional data are needed to evaluate the effectiveness of Vyxeos in t-AML and AML-MRC. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase 1 Study of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide in Combination with Polatuzumab (ViPOR-P) in Relapsed/Refractory B-Cell Lymphoma: Preliminary Analysis of Safety and Efficacy

Background: Diffuse large B-cell lymphoma (DLBCL) is often curable with frontline chemotherapy; however, pts with relapsed/refractory (R/R) disease and those who fail CAR-T therapy have poor overall outcome. Oral small molecule targeted agents can disrupt key survival pathways in DLBCL, but fail to induce deep or durable responses as monotherapy. We have previously shown that ViPOR is safe and active in DLBCL, with preferential activity in non-GCB DLBCL and HGBCL-DH (Melani et al. Blood. 2020). Synergistic activity has also been demonstrated with MMAE, the chemotherapy payload of Polatuzumab (Pola), with ViPOR in pre-clinical DLBCL cell lines (unpublished data). We hypothesized that additional genotoxic stress with Pola will further leverage efficacy and time-limited, cyclic dosing will limit the hematologic toxicity of the regimen. Methods: R/R aggressive B-cell lymphoma pts with adequate organ function were eligible. In phase 1, a 3+3 design was used to determine the maximum tolerated dose (MTD) of 3 dose-levels (DLs) of Pola IV D2 and venetoclax (Ven) PO D2-14 (DL1: 1.4mg/kg + 600mg, DL2: 1.8mg/kg + 600mg, and DL3: 1.8mg/kg + 800mg) in combination with fixed-dose ibrutinib 560mg PO D1-14, prednisone 100mg PO D1-7, obinutuzumab 1000mg IV D1-2, and lenalidomide 15mg PO D1-14. An expansion cohort was included at the MTD for further analysis of safety and efficacy. ViPOR-P q21d x 6 cycles (C) was given without maintenance or planned consolidation. All pts received TLS, PCP, HSV, and G-CSF prophylaxis (ppx) with VTE ppx per investigator discretion. Baseline CT, PET, BM, and tumor biopsy were performed with CT scans after C2, 4, and 6 and PET after C6 or at time of suspected complete response (CR). Surveillance CT was performed q3m for 1y, q4m x 1y, q6m x 1y, then annually x 2y. Results: 15 pts were enrolled and treated in the dose-escalation cohort; 3 at DL1, 6 at DL2, and 6 at DL3. Lymphoma subtypes included DLBCL NOS (60%) and HGBCL-DH (40%). In 9 DLBCL NOS pts, 11% were GCB and 89% non-GCB subtype by IHC. Three (20%) pts had transformed disease. Median age was 51y (range 39-83), with stage III/IV disease in 80%, elevated LDH in 80%, and >2 extranodal sites of disease in 67%. Nine (60%) pts had high-intermediate/high-risk IPI. Median prior therapies were 2 (range 1-6), with prior BTKi in 27%, Pola in 7%, and CAR-T in 20%. Ten (67%) pts were primary refractory (i.e., <CR to frontline tx) and 8 (53%) of pts were refractory (i.e., <PR) to last tx. One dose-limiting toxicity (DLT) of prolonged G4 thrombocytopenia occurred at DL3, but no other DLTs were noted. Pola 1.8mg/kg and Ven 800mg were identified as the MTD and safe doses for use in the expansion cohort. Heme AEs were most common and included G3-4 (% cycles) thrombocytopenia (17%), anemia (7%), and neutropenia (5%). No cases of febrile neutropenia occurred across 58 cycles. The only non-heme G3-4 AE occurring in >10% pts was hypokalemia (29%), with all pts experiencing any grade hypokalemia requiring replacement. Other common non-heme AEs (% pts) included diarrhea (71%), increased LFTs (64%), nausea (50%), hypomagnesemia (43%), and rash (43%). VTE occurred in 7% with no a.fib or major bleeding observed. No events of TLS or treatment-related mortality occurred. Dose reductions and delays occurred in 3% and 5% of cycles, respectively. Of 12 pts off-tx, 7 completed all 6C, 3 experienced disease progression, and 1 each came off-tx per investigator discretion or unacceptable AE. Of 15 enrolled pts, 14 are evaluable for response with an overall response rate (ORR) and CR rate of 64% (9/14) and 36% (5/14), respectively (Fig 1A). With a median potential f/u of 7.4m, median TTR in responding pts was 1.35m, with 8 (89%) of 9 total responses ongoing (Fig 1B). One HGBCL-DH pt relapsed by imaging at 10.6m, 2 PR pts received consolidative XRT with allo-HSCT, and 2 PR pts remain on-tx. PFS and OS at 6m was 69.8% and 75%, respectively. Conclusion: ViPOR-P is safe without significant additional toxicity compared to ViPOR, and Pola 1.8mg/kg and Ven 800mg were taken forward in the ongoing expansion cohort. Most common G3-4 AEs were hematologic with no febrile neutropenia observed with the use of G-CSF ppx. Fixed-duration ViPOR-P x 6C without maintenance led to CR in 5 (42%) of 12 off-tx DLBCL pts with 80% CRs ongoing from 3.7-9.3m. A randomized phase 2 trial is planned to further elucidate the safety and efficacy of Pola in combination with ViPOR across R/R DLBCL and within pre-defined molecular and genetic subtypes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR) in Relapsed and Refractory Follicular Lymphoma: Analysis of Safety, Efficacy, and Minimal Residual Disease

Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR) in Relapsed and Refractory Follicular Lymphoma: Analysis of Safety, Efficacy, and Minimal Residual Disease

X-ray Target Shielding and Leakage Radiation Inside the Treatment Capsule of the Zap-X.

The ZAP-X represents the first-of-its-kind "self-shielded" therapeutic radiation device, which by novelty, challenges regulators to accommodate it within the existing regulatory framework for radiation protection. To facilitate informed regulatory interpretation, X-ray radiation leakage from the ZAP-X was measured inside the shielded treatment capsule at the level of the patient and X-ray target plane. Measurements were performed on a clinically commissioned system calibrated for reference conditions to deliver 1cGy/MU. Radiation was measured with a FLUKE 451 survey meter and a RadCal ionization chamber as both exposure and dose and presented as a percentage of the system reference dose. Measurements were taken at thirteen locations, eight in the patient plane and five in the X-ray target plane. The results showed a maximum X-ray leakage of 0.000986% in the patient plane and 0.000907% in the target plane. These results are 30 - 100 times lower than existing recommendations as referenced by IEC guidelines standard 60601-2-1 (2020) for radiotherapy linear accelerators (LINACs). Although most conventional LINACs apply a safety factor of 2-5 to the design of collimator shielding and patient dose sparing, the ZAP-X delivers less than 10% of the patient whole body dose compared to this standard, originating from the X-ray target. Even though the ZAP-X intensity modulated radiation therapy (IMRT) factor is significantly higher than conventional Linacs, the absolute dose originating from leakage radiation remains lower by 25. The amount of unintended dose received by the patient's body distant from the isocenter is of interest from the perspective of both clinical and radiation safety. As this whole-body dose is decreased, the resulting treatment-related cancer incidence and mortality rates are decreased accordingly.

Deaths and adverse events from adjuvant therapy with immune checkpoint inhibitors in solid malignant tumors: A systematic review and network meta-analysis.

By prolonging overall survival and reducing disease recurrence rates, immune checkpoint inhibitors (ICIs) are an emerging adjuvant therapy option for patients with resectable malignant tumors. However, the safety profile (deaths and adverse events [AEs]) of adjuvant ICIs has not been fully described. We searched the literature for phase III randomized clinical trials that compared PD-1, PD-L1, and CTLA-4 inhibitors in solid malignant tumors. Incidences of death, discontinuation, AEs of any cause, treatment-related adverse events (TRAEs), and immune-related adverse events (IRAEs) were extracted for the network meta-analysis. Network meta-analyses with low incidence and poor convergence are reported as incidences with 95% confidence intervals (95% CIs). Ten randomized clinical trials that included 9243 patients who received ICI adjuvant therapy were eligible. In total, 21 deaths due to TRAEs were recorded, with an overall incidence of 0.40% (95% CI: 0.26-0.61). The treatment-related mortality rates for ipilimumab (0.76%, 95% CI: 0.31-1.55) and atezolizumab (0.56%, 95% CI: 0.18-1.31) were higher than for pembrolizumab (0.24%, 95% CI: 0.10-0.56) and nivolumab (0.30%, 95% CI: 0.08-0.77). The most frequent causes of death were associated with the gastrointestinal (0.10%, 95% CI: 0.04-0.24) and pulmonary (0.08%, 95% CI: 0.03-0.21) systems. Compared with the control arm, we found that nivolumab (odds ratio [OR]: 2.73, 95% CI: 0.49-15.85) and atezolizumab (OR: 12.43, 95% CI: 2.42-78.48) caused the fewest grade ≥3 TRAEs and IRAEs. Commonly reported IRAEs of special interest were analyzed, and two agents were found to have IRAEs with incidences >10%, i.e., hepatitis for atezolizumab (14.80%, 95% CI: 12.53-17.32) and hypophysitis for ipilimumab (13.53%, 95% CI: 11.38-15.90). Ipilimumab and atezolizumab were correlated with higher treatment-related death rates than pembrolizumab and nivolumab, in which the gastrointestinal and pulmonary systems were mostly involved. Regarding severe TRAEs and IRAEs, nivolumab and atezolizumab are likely to be the safest agent, respectively. This study will guide clinical practice for ICI adjuvant therapies.

Clinical Dilemmas in the Treatment of Elderly Patients Suffering from Hodgkin Lymphoma: A Review.

Elderly patients make up a significant number of cases of newly diagnosed Hodgkin lymphoma. However, unlike in young patients, the outcomes of elderly patients are poor, and they are under-represented in phase III trials. Prior to treatment initiation, geriatric assessment should ideally be performed to address the patient's fitness and decide whether to pursue a curative or palliative approach. The ABVD regimen is poorly tolerated in unfit patients, with high treatment-related mortality. Alternative chemotherapy approaches have been explored, with mixed results obtained concerning their feasibility and toxicity in phase II trials. The introduction of brentuximab vedotin-based regimens led to a paradigm shift in first- and further-line treatment of elderly Hodgkin lymphoma patients, providing adequate disease control within a broader patient population. As far as checkpoint inhibitors are concerned, we are only just beginning to understand the role in the treatment of this population. In relapsed/refractory settings there are few options, ranging from autologous stem cell transplantation in selected patients to pembrolizumab, but unfortunately, palliative care is the most common modality. Importantly, published studies are frequently burdened with numerous biases (such as low numbers of patients, selection bias and lack of geriatric assessment), leading to low level of evidence. Furthermore, there are few ongoing studies on this topic. Thus, elderly Hodgkin lymphoma patients are hard to treat and represent an unmet need in hematologic oncology. In conclusion, treatment needs to be personalized and tailored on a case-by-case basis. In this article, we outline treatment options for elderly Hodgkin lymphoma patients.