Hematopoietic Stem Cell Transplantation Rates Research Articles

Trial in Progress: Venetoclax in Combination with ASTX727, an All-Oral Therapy for Chronic Myelomonocytic Leukemia and Other MDS/MPN with Excess Blasts (VICTORY MDS/MPN): A Randomized, Phase 2 Trial

Background and Significance: The rare nature and diagnostic difficulty associated with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has limited the inclusion of patients (pts) with these diseases, other than chronic myelomonocytic leukemia (CMML), in relevant clinical trials. This has resulted in the complete lack of approved agents for the treatment of pts with non-CMML MDS/MPN. Moreover, ASTX727 (oral decitabine-cedazuridine) was approved for CMML based on a study of only 16 pts with CMML. A larger study of CMML and non-CMML MDS/MPN is needed. MDS/MPNs appear to be BCL2-dependent (Bogenberger et al., 2015; Jilg et al., 2016), but data for venetoclax combination therapy are derived from retrospective analyses of relapsed/refractory disease (Cortes et al. 2019; Hammond et al., 2020) or single-arm studies not dedicated to MDS/MPN (NCT04655755, Venugopal et al. 2021). Venetoclax exposures are not affected by coadministration of ASTX727 and predict responses similar to historical data (Mannis et al. 2021). Based on these promising early data and the critical need, we proposed a randomized study of ASTX727 alone or in combination with venetoclax for pts with MDS/MPN and >5% blasts. Study Design and Methods: This is a National Cancer Institute-sponsored, multi-center, international, randomized phase 2 study (NCT05600894, NCI 10538) designed to evaluate the efficacy of ASTX727 alone or in combination with venetoclax in pts with newly diagnosed MDS/MPN with >5% marrow blasts. Key eligibility criteria include allowing hydroxyurea cytoreduction to a WBC <10,000/mm 3 for proliferative disease and excluding pts with need for emergent disease-directed therapy as well as prior therapy for myeloid malignancy other than hydroxyurea or thrombopoietic/erythropoietin stimulating agents. Pts will be randomized 1:1 to receive either ASTX727 alone (Days 1-5) or in combination with venetoclax, initially administered with a 3-day dosing ramp-up and given for 14 days per 28-day cycle (Figure 1). Pts are stratified by disease subtype, specifically CMML and non-CMML MDS/MPN. The primary endpoint is the rate of complete remission (adapted from the MDS/MPN-specific response criteria developed by Savona et al. 2015). Secondary endpoints include the overall response rate, overall survival, progression-free survival, allogeneic hematopoietic stem cell transplantation rate, clonality at time of hematologic remission, number of red cell and platelet transfusions required and toxicity of ASTX727 versus ASTX727 + venetoclax. Pts randomized to the ASTX727 monotherapy arm and without response after 4 cycles of therapy, or with progressive disease after an initial response, cross over to the ASTX727 + venetoclax arm. A futility analysis is planned for each cohort (first 18 and 13 pts in each treatment arm for the CMML and non-CMML cohorts, respectively). We assume that 85% and 90% of pts in the CMML and non-CMML MDS/MPN cohorts, respectively, randomized to the ASTX727 monotherapy arm will not achieve the primary endpoint and will cross over to the ASTX727 + venetoclax combination arm. The estimated accrual time of a total of 70 pts with CMML and 50 pts with non-CMML MDS/MPN will require about 2.9 and 2.1 years, respectively. Planned integrated studies include the use of an apoptosis multiplex immunoassay to evaluate how the addition of a BCL-2 inhibitor will influence the ability of ASTX727 to induce apoptosis and if particular thresholds of apoptosis are predictive of clinical response. Planned exploratory studies include the use of: 1) RNA-seq to evaluate if differences in baseline transcriptional programs appear to be predictive of response to ASTX727 and ASTX727+venetoclax, 2) next generation (Oncomine Comprehensive Assay (OCAv3)/whole exome sequencing to uncover biomarkers predictive of response/outcome, validate risk modeling to stratify these pts and detect/monitor measurable residual disease (MRD) on serial marrow samples that can predict depth of response with translation in improvement in event-based endpoints, and 3) circulating tumor DNA as a non-invasive means (i.e., without need for a marrow evaluation) of prospective MRD detection for prognostic use. This ongoing, randomized study may inform frontline therapeutic options, provide prospective data for venetoclax combination after HMA failure, and generate striking correlative science for pts with “high risk” MDS/MPN.

Evaluation of Transplanted Stem Cell Dynamic Variables in the Bone Marrow of Children with Malignancies

Objective: According to risk classifications, the transplant of healthy hematopoietic stem cells in the bone marrow is a priority treatment option for hematopoietic diseases. The effectiveness of hematopoietic stem cell transplantation after bone marrow transplantation is largely dependent on the capacity of the bone marrow microenvironment to accept transplanted cells. Detailed analysis of hematopoietic stem cell kinetics after transplantation is very important, as initial transplantation of hematopoietic stem cells affects prognosis. In this study, hematopoietic stem and progenitor cell percentage values were evaluated together with other transplantation-related parameters to determine the capacity of stem cell dynamic variables in the bone marrow. Methods: Dynamic variables in hematopoietic stem cell fate in bone marrow transplantation include many parameters; hematopoietic stem cell transplantation rates in the apheresis product of 13 patients and cell counts per kilogram and engraftment times, CD34+ cell rates, CD34+ cell counts per kilogram, chimerism rates, Graft-versus-Host Disease grades, white blood cell counts, and post-transplant relapse status. In the apheresis products collected from the patients before transplantation, hematopoietic stem and progenitor cells were identified by the immunophenotypic barcode "CD34+, CD38-, CD45RA-, CD90+, CD49f+", and data analysis was performed with the BD FACSDivaTM software by studying on the BD FACSCanto II flow cytometer device. Results: According to the results of the pearson correlation analysis (non-parametric correlations), a strong positive and significant relationship was found between the number of hematopoietic stem cell transplantation per kg and the percentage of hematopoietic stem cell transplantation of the patients (r=.733, p<.05). According to the results of the analysis, there was a moderately significant and positive relationship (r=.631, p<.05) between the percentage of hematopoietic stem cell transplantation and platelet engraftment time, while there was a strong inverse relationship between erythrocyte engraftment time (r=-.730, p<.01). A strong positive and significant relationship was found between the number of Hematopoietic stem cell transplantation cells per kilogram infused into the patients and the platelet engraftment times (r=.780, p<.05). Conclusion: This study confirms that a mean cell dose of hematopoietic stem and progenitor cells ≥ 2.57 x 106/kg infused provides rapid short- and long-term platelet engraftment in pediatric patients undergoing autologous and allogeneic transplantation. This study is important in terms of revealing the possible relationship between pulling forward the platelet engraftment time and the number and percentage of Hematopoietic stem and progenitor cells in our transplanted patients. It is also important that a statistically significant inverse relationship was determined between HSPC values and mean erythrocyte engraftment times.

A Multi-Center Open-Labeled Phase II Study of Intensive Salvage Therapy Followed By Enasidenib Maintenance for Patients with Relapsed/Refractory IDH2mutant AML

Introduction: Patients with relapsed/refractory acute myeloid leukemia (R/R AML) have limited therapeutic options and effective management remains clinical challenge. For medically fit patients, salvage therapy with an intensive chemotherapy regimen is the standard of care with remission rates of about 40-50%. Long-term survival is achievable only with disease control followed by allogeneic hematopoietic stem cell transplantation (HCT). A majority of patients with R/R AML who achieve a morphologic clinical remission with salvage chemotherapy frequently harbor detectable clonal events that act as a reservoir for disease relapse. Relapsed/refractory isocitrate dehydrogenase 2 (IDH2) mutant AML patients who undergo cytarabine based salvage chemotherapy will largely retain detectable IDH2 mutations and enasidenib maintenance therapy offers an attractive and tolerable approach to maintenance for such patients. Enasidenib (AG221) is a first-in-class, selective, potent inhibitor of the neomorphic activity of mutant IDH2 enzyme. It is FDA approved as monotherapy for R/R AML with a time to response of approximately 2 months, but there is limited data on the use of this agent following salvage chemotherapy. In the upfront setting, the combination of enasidenib with induction chemotherapy has demonstrated high response rates, providing rationale for this approach (and tolerability with the combination) in the R/R population. Methods: To understand the impact of tailored consolidation following salvage chemotherapy in fit R/R AML we designed a multi-center, phase II trial with 2 cohorts. Cohort assignment is based upon the investigators assignment of patients eligibility (cohort 1.) for allogeneic HCT or (cohort 2) no allogeneic HCT. The main inclusion criteria are, (a.) age over 18 years (b.) received salvage cytarabine based chemotherapy or venetoclax combined with hypomethylating agents (HMA) or 2 or more cycles of HMA for confirmed R/R AML (c.) achieved at least >50% reduction in blast percentage in a nadir marrow from salvage chemotherapy and (d.) adequate organ function and lack of acute life threatening illness. Patients will have received the investigator's choice of salvage therapy and subsequently undergo bone marrow assessment with protocol sampling. Patients confirmed to have obtained a remission will then begin enasidenib 100mg once a day starting between 14 and 60 days after starting salvage therapy. Patients in cohort 1 will receive 1-4 cycles of enasidenib and proceed with HCT; enasidenib can be re-initiated between D30-100 following HCT for a planned total of 24 cycles. Cohort 2 will continue enasidenib maintenance until progression/death or relapse (Schema: Fig 1). Study Endpoints: The primary endpoint of the study to determine the effect of enasidenib maintenance therapy following salvage induction therapy for IDH2 R/R AML, we will evaluate EFS at 12 months separately in the two cohorts of the study. Secondary endpoints include (1) Rate of successful HCT of the subjects enrolled on the study (2) Median duration of maintenance therapy in both the study arms & (3) Overall survival at 12 and 24 months in each cohort. The efficacy of the treatment will be assessed using Simon (1989) optimal two-stage, single arm, unblinded Phase II trials allowing for early termination for futility. This design has a 90% power to detect a 20% improvement rate compared to historical data, while controlling to 10% probability of erroneously findings. A total of 39 (C1) + 25 (C2) = 64 evaluable patients will be enrolled. Interim safety analysis will be done after enrollment of the first 28 patient in C1 and 17 patients in C2. Conclusion: This study is currently is open and enrolling patients at multiple collaborative institutions to answer the key question of efficacy of enasidenib maintenance following salvage chemotherapy. Correlative studies are being performed to understand minimal residual disease in IDH2 mutant AML and its clonal architecture. Disclosures Carraway: BMS: Consultancy, Other: Research support, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; ASTEX: Other: Independent Advisory Committe (IRC); Abbvie: Other: Independent Advisory Committe (IRC); Takeda: Other: Independent Advisory Committe (IRC); Stemline: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Griffiths:Novartis: Honoraria, Research Funding; Boston Biomedical: Honoraria; Genentech Inc: Research Funding; Astex Pharmceuticals: Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; AbbVie Inc: Honoraria; Persimmune: Research Funding.

Reduced-Toxicity (BuFlu) Conditioning Is Better Tolerated but Has a Higher Second Transplantation Rate Compared to Myeloablative Conditioning (BuCy) in Children with Inherited Metabolic Disorders.

Hematopoietic stem cell transplantation (HCT) is a primary treatment for various inherited metabolic disorders (IMDs). Achieving stable and sustained engraftment while minimizing transplantation-related morbidity and mortality is critical to optimizing outcomes for IMDs. Traditional regimens have used myeloablative approaches, primarily busulfan and cyclophosphamide (BuCy), which is associated with significant regimen-related toxicity. Alternatively, reduced-toxicity regimens, such as busulfan and fludarabine (BuFlu), have been proposed to offer similar efficacy with reduced toxicities. We compared transplantation-related outcomes with BuCy-based and BuFlu-based conditioning in patients with IMDs. We retrospectively analyzed the University of Minnesota's transplantation database for patients with IMDs who underwent HCT using a BuCy (with alemtuzumab) or BuFlu (with antithymocyte globulin) preparative regimen between March 2008 and September 2017. Overall survival (OS), event-free survival (EFS), and incidence of neutrophil and platelet recovery were determined using standard definitions. Complications such as graft failure, sinusoidal obstruction syndrome, hemorrhagic cystitis, and respiratory failure were compared. Graft failure includes primary and secondary aplastic graft failure with and without autologous recovery. The incidence of viral infections post-transplantation in the 2 regimens was also determined. A total of 99 patients underwent HCT for IMDs during the study period. Sixty-four patients received BuCy conditioning, and the other 35 received BuFlu. Hurler syndrome (46%) and adrenoleukodystrophy (43%) were the most common IMDs, and umbilical cord blood was the most common graft source (74%). One-year OS was similar in the 2 groups (81.2% in BuCy versus 85.5% in BuFlu; P=.8), with an EFS of 75% versus 63%, respectively. The 2 groups also had similar incidences of grade III-IV acute GVHD (9% versus 6%; P=.5) and chronic GVHD (9% versus 7%; P=.67). Neutrophil and platelet recovery were similar in the 2 groups, with a significantly shorter duration of hospital stay noted in the BuFlu cohort (median, 21 days versus 34 days; P=.002). The cumulative incidence of graft failure was significantly higher in the BuFlu group (29% versus 14%; P=.08), as was the rate of second HCT (27% versus 3%; P=.001). The incidences of adenoviral infection (14% versus 0%; P=.02) and hemorrhagic cystitis (23% versus 3%; P=.01) were higher in the BuCy group. T cell engraftment occurred significantly sooner with BuCy conditioning until 1-year post-transplantation, but donor myeloid engraftment was similar in the 2 groups. Our data indicate that reduced-toxicity conditioning is associated with lower rates of infection and other transplantation-related complications but is concerning for a higher rate of graft failure in patients with IMDs. Alternate immunosuppressive agents and novel techniques should be considered to minimize toxicities and reduce complications.

Reduced Toxicity Conditioning Is Better Tolerated but Has Higher Graft Failure Compared to Myeloablative Conditioning in Children with Inherited Metabolic Disorders

Background: Hematopoietic stem cell transplantation (HCT) is a primary treatment option for various inherited metabolic diseases (IMDs). Successful engraftment is crucial for favorable survival and functional outcomes and correlates with optimal conditioning in these patients with an intact immune system. Traditional regimens have used myeloablative Busulfan and Cyclophosphamide (BuCy) which is associated with significant potential morbidity. Alternate reduced toxicity regimens, like Busulfan and Fludarabine (BuFlu), are often utilized to reduce treatment related toxicities.Objective: To compare outcomes and complications with BuCy and BuFlu based conditioning regimens in patients with IMDs.Methods: This is the largest single institution retrospective analysis of University of Minnesota's transplant database for patients with IMDs who underwent HCT using BuCy + campath or BuFlu + ATG based preparative regimen from March 2008 to September 2017. Incidence of neutrophil and platelet recovery were determined using standard definitions. Complications such as graft failure, sinusoidal obstruction syndrome, hemorrhagic cystitis and respiratory failure were compared. Graft failure includes primary aplastic graft failure, primary graft failure with autologous recovery, secondary aplastic failure and secondary graft failure with autologous recovery. Incidence of viral infections post-transplant comparing two regimens were also determined.Results: Total of 99 patients were studied who underwent HCT for IMDs during the study period. Sixty-four received BuCy conditioning and 35 received BuFlu. Hurler syndrome (46%) and adrenoleukodystrophy (43%) were most common IMDs transplanted and umbilical cord blood was the most common donor source (74%). One-year overall survival was similar in both groups (81.2% in BuCy vs. 85.5% in BuFlu; p=0.8) with a similar incidence of grade 3-4 acute GVHD (9% in BuCy vs. 6% in BuFlu; p=0.5) and chronic GVHD (9% in BuCy vs. 7% in BuFlu; p=0.67) in the two groups. Neutrophil and platelet recovery were similar in both groups with significantly shorter duration of hospital stay noted in BuFlu group (median 21 d vs. 34 d, p = 0.002). The cumulative incidence of graft failure was higher with BuFlu conditioning (29% vs 14%, p= 0.08, Figure 1a). Significantly higher rates of second HCT was noted following BuFlu conditioning (27% vs. 3%, p= 0.001; Figure 1b). The incidence of adenoviral infection (14% vs. 0%, p=0.02) and hemorrhagic cystitis (23% vs. 3%, p=0.01) were notably higher in the BuCy group. Though donor myeloid engraftment was similar in both groups, donor T-cell engraftment occurred sooner with BuCy conditioning until 1-year post transplant (Figure 2).Conclusions: Reduced toxicity conditioning leads to lower rates of infections and other transplant related complications, but is associated with a high rate of graft failure in patients with IMD. Alternate immune suppressive agents should be considered to reduce graft failure and minimize toxicities. Alternate donor options, including expanded UCB, should also be considered to improve engraftment in patients with IMDs. [Display omitted] DisclosuresShanley:Magenta Therapeutics: Research Funding. Miller:Sangamo Therapeutics: Employment. Orchard:Magenta Therapeutics: Research Funding.

Abstract B83: Survival of ethnic and racial minority patients with multiple myeloma treated with first-generation immunomodulatory and proteasome-inhibiting medications

Abstract Introduction: Survival for patients with multiple myeloma has increased in the early 21st century. However, population-based studies have suggested that patients of minority ethnic and racial background may not have benefited as much as non-Hispanic white patients. It has been hypothesized that the newer medications may not be as effective in minority patients as in non-Hispanic whites. Methods: To test this hypothesis, we examined survival in patients participating in clinical trials for registration of one of the newer medications with the FDA. In order to minimize the impact of prior therapy and differences in hematopoietic stem cell transplantation rates, only trials examining outcomes in patients with newly diagnosed multiple myeloma who were transplant ineligible were included. Because clinical trial participation by people of minority ethnic or racial background is low, race/ethnicity was categorized as “non-Hispanic white” (nHW), “Asian/Pacific Islander” (API), and “other race/ethnicity.” People of Hispanic ethnicity were included in the “other race/ethnicity” category regardless of race. Results: Five studies involving treatment of newly diagnosed myeloma patients were identified, with a total of 3,407 subjects treated. Four of these trials examined outcomes for patients receiving immunomodulatory drugs (thalidomide and lenalidomide); one examined outcomes for patients receiving bortezomib. Participation by minorities in individual trials ranged from <1% to 17%. Asian/Pacific Islanders were more likely to have high ISS stage and less likely to have favorable cytogenetics compared to other ethnic and racial groups. Non-Hispanic whites were slightly older compared to other ethnic groups (72.0 years for nHW versus 69.5 for API and 69.0 for others). Patients of API background had a numerically slightly higher risk of mortality (hazard ratio of 1.15) compared with non-Hispanic whites after stratification for treatment and study, but the difference was not statistically significant (p=0.28). Patients of other ethnic and racial backgrounds had a lower risk of mortality with a hazard ratio of 0.76 (p=0.03) after stratification for treatment and study and 0.78 (p=0.05) after additional stratification for stage. Conclusions: We conclude that the efficacy differences in treatment between races are minor and do not account for the differences in survival observed in population-based studies. People of minority race or ethnicity other than API with myeloma showed better survival in clinical trials, despite lower survival on the population level for most minorities. Other factors such as access to care may explain the observed population level differences. Citation Format: Elizabeth Dianne Pulte, Lei Nie, Nicole Gromley, Kirsten Goldberg, Amy McKee, Ann Farrell, Richard Pazdur. Survival of ethnic and racial minority patients with multiple myeloma treated with first-generation immunomodulatory and proteasome-inhibiting medications [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B83.

Hematopoietic stem cell transplantation rates and long‐term survival in acute myeloid and lymphoblastic leukemia

Allogeneic stem cell transplantation (alloSCT) reduces relapse rates in acute leukemia, but outcome is hampered by toxicity. Population-based data avoid patient selection and may therefore substitute for lack of randomized trials. We evaluated alloSCT rates within the Swedish Acute Leukemia Registry, including 3899 adult patients diagnosed from 1997 through 2006 with a coverage of 98% and a median follow-up of 6.2 years. AlloSCT rates and survival decreased rapidly with age >55 years. The 8-year overall survival (OS) was 65% in patients <30 years and 38% in patients <60 years and was similar for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Among 1073 patients <60 years, alloSCT was performed in 42% and 49% of patients with AML and ALL, respectively. Two-thirds of the alloSCTs were performed in first complete remission, and half used unrelated donors, the same in AML and ALL. Regional differences in management and outcome were found: 60% of AML patients <40 years received alloSCT in all parts of Sweden, but two-thirds of AML patients 40-59 years had alloSCT in one region compared with one-third in other regions (P<.001), with improved 8-year OS among all AML patients in this age cohort (51% vs 30%; P = .005). More Swedish AML patients received alloSCT, and long-term survival was better than in recently published large international studies, despite our lack of selection bias. There was no correlation between alloSCT rate and survival in ALL. In adult AML patients <60 years of age, a high alloSCT rate was associated with better long-term survival, but there was no such correlation in ALL.

Access to hematopoietic stem cell transplantation

The purpose of the current study was to determine whether the use of hematopoietic stem cell transplantation (HCT) to treat leukemia, lymphoma, or multiple myeloma (MM) differs by race and sex. The annual incidence of leukemia, lymphoma, and MM was estimated in the United States in people aged <70 years by race and sex using the Surveillance, Epidemiology, and End Results (SEER) cancer registry between 1997 and 2002 and US census reports for the year 2000. The annual incidence of autologous, human leukocyte antigen (HLA) identical sibling, and unrelated HCT performed in these groups was estimated using Center for International Blood and Marrow Transplant Research data from 1997 through 2002. Logistic regression analysis was used to calculate the age-adjusted odds ratio (OR) of receiving HCT for Caucasians versus African Americans and for men versus women. The likelihood of undergoing HCT was found to be higher for Caucasians than for African Americans (OR, 1.40; 95% confidence interval [95% CI], 1.34-1.46). This difference existed for each type of HCT: autologous (OR, 1.24; 95% CI, 1.19-1.30), HLA identical sibling (OR, 1.59; 95% CI, 1.46-1.74), and unrelated donor (OR, 2.02; 95% CI, 1.75-2.33). Overall, men were more likely than women to receive HCT (OR, 1.07; 95% CI, 1.05-1.1 [P<.0001]); however, this difference was found to be significant only for autologous HCT (OR, 1.10; 95% CI, 1.07-1.13 [P<.0001]). HCT is more frequently used to treat leukemia, lymphoma, and MM in Caucasians than in African American individuals. African Americans have lower rates of both autologous and allogeneic HCT, indicating that donor availability cannot fully explain the differences. Women are less likely than men to receive autologous HCT for reasons unexplained by age or disease status.

Predictability of hematopoietic stem cell transplantation rates

Hematopoietic stem cell transplantation (HSCT) is a complex and expensive procedure. Trends in the use of this procedure have appeared erratic in the past. Information on future needs is essential for health care administrators. We analyzed the evolution of transplant rates, e.g. numbers of transplants per 10 million inhabitants, in Europe from 1990 to 2004 for all major disease categories and used Gross National Income (GNI) per capita, team density (numbers of teams per 10 million inhabitants) and team distribution (numbers of teams per 10,000 km2) to measure the impact of economic factors in participating countries. Trends were compared by regression analyses, and countries were grouped by World Bank definitions into high, middle and low income categories. Transplant rates increased over time with nearly linear trends, in clear association with GNI per capita (R2=0.72), and distinct by World Bank category within a narrow window of variation for both autologous HSCT (R2=0.95, 0.98 and 0.94 for high, middle and low income categories, respectively) and allogeneic HSCT (R2=0.99, 0.96 and 0.95 for high, middle and low income categories, respectively) when breast cancer (autologous) and chronic myeloid leukemia (allogeneic) were excluded. Team density (R2=0.72) and team distribution (R2=0.51) were also associated with transplant rates. Transplant rates for HSCT in Europe are highly predictable. They are primarily influenced by GNI per capita. The absence of saturation and a nearly linear trend indicate that infrastructure lags behind medical needs. Isolated changes in single disease entities can easily be recognized.