Candidates For Autologous Stem Cell Transplantation Research Articles

Checkpoint Inhibitors Prior to Autologous Stem Cell Transplantation for Relapsed/ Refractory Hodgkin Lymphoma

Aim: To present the evolution of our patients treated with checkpoint inhibitors before high-dose chemotherapy and autologous stem cell transplantation (ASCT) and to compare the results with data from the literature. Material and methods: We evaluate 3 patients with relapsed/refractory Hodgkin’s Lymphoma, who failed to achieve complete remission after 2 or more lines of salvage chemotherapy and were treated with anti PD1 inhibitors as a bridging therapy to autologous stem cell transplant. To evaluate the treatment response, we used PET CT scan before and 100 days after ASCT. Results: In our study, heavily pre-treated and chemo-refractory patients had increased response rates to conditioning chemotherapy followed by ASCT given after exposure to immune-checkpoint inhibitors. All 3 patients remain in complete response at 14 months, 20 months and respectively 32 months of follow-up. Conclusions: High-dose chemotherapy and ASCT can be curative for many patients with relapsed or refractory Hodgkin’s Lymphoma (HL), but the outcome depends on disease status at ASCT. Patients who have chemorefractory disease, particularly those who fail more than 2 lines of salvage therapy, are considered poor candidates for ASCT. Checkpoint inhibitors are routinely employed in relapsed/refractory classical Hodgkin lymphoma. The results from our center are similar with those from several studies which have suggested that treatment with anti PD1 can sensitize previously chemorefractory HL patients to subsequent high-dose therapy and ASCT.

Assessing the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) in Risk-Stratifying Multiple Myeloma Patients for Autologous Stem Cell Transplantation

Background: Hematopoietic stem cell transplant (SCT) is a high-intensity treatment that can cause psychological distress. Pre-transplant psychosocial screening is commonly used to assess mental health, social support, compliance, and health behaviors in HCT centers. However, the optimal standardized approach to psychosocial screening is still being defined. Some studies have shown that pre-transplant psychosocial assessments can predict overall survival (OS) after SCT, while others have found associations with non-relapse mortality (NRM) but not with OS. Single-institution reports consistently indicate that pre-HCT psychosocial assessments are associated with the length of SCT hospitalization and readmission rate. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is an established tool in the solid organ transplant field that can be used to assess and quantify psychosocial risk, that can help in patient selection and pre-transplant preparation. Objective: This study aimed to validate the SIPAT as a standardized psychological assessment in patients with multiple myeloma (MM) undergoing autologous SCT (ASCT). The primary goal was to analyze the impact of psychosocial risk, as measured by the SIPAT score, on the length of hospital stay and readmission rates within 100 days post-discharge. Secondary outcomes included the risk of infections, progression-free survival (PFS), and overall survival (OS). Methods: This retrospective, single-center study included 87 patients with MM who underwent ASCT between 2019 and 2022 at University Hospitals Seidman Cancer Center. Patient and disease characteristics were collected, and SIPAT scores were recorded for all patients. Patients were grouped based on their SIPAT scores as “Excellent” (score ≤ 6) or “Good” (score > 6). Hospitalization duration during transplant, readmissions, and infections within the first 100 days after ASCT were used as indicators of treatment-related toxicity. Results: 30 patients had an “Excellent” SIPAT score (mean score: 3.47, SD 1.81), while 57 had a “Good” score (mean score: 11.81, SD 5.92). Both groups exhibited similar sex and race distribution, BMI, and KPS scores. The “Excellent” SIPAT group had more patients with HCT-CI scores of 0-2. Both groups had comparable ISS staging and high-risk cytogenetics, along with similar prior lines of treatment and disease status at the time of transplant. Patients in the “Good” SIPAT score group had a higher number of CD34+ cells infused per kg. No significant differences were observed between the groups in terms of engraftment time, hospitalization duration, or rates of hospitalizations and infections within the first 100 days after transplant. Univariate analysis of risk of readmissions showed that BMI had a significant effect (HR 1.09, 95% CI 1.02-1.16, p=0.009) for each unit increase and HCT-CI had a significant effect (HR 5.56, 95% CI 1.39-22.24, p=0.015) for HCT-CI score 3+ compared to 0-2. However, in the multivariable model, these effects did not persist. Conclusions: Although the SIPAT tool is widely used for evaluating different organ transplants, including HCT, a high SIPAT score alone may not be sufficient to risk-stratify candidates for ASCT in MM. Further research and evaluation are warranted to better understand the true predictive value of pre-transplant psychosocial assessments.

High-Dose Methotrexate Containing Induction Chemotherapy Followed By Nivolumab Consolidation in Older (≥ 65) Patients with Previously Untreated Primary CNS Lymphoma

Introduction: High-dose methotrexate (HD-MTX)-containing chemotherapy followed by either autologous stem cell transplant (ASCT) or whole-brain irradiation (WBI) is widely considered the standard for primary CNS lymphoma (PCNSL) treatment. However, many older frail patients with PCNSL are unable to undergo ASCT or WBI due to increased risk of treatment-related toxicity, such as infections and neurotoxicity. Without consolidation, survival outcomes are significantly worse, with a 3-year progression free survival (PFS) rate of ~ 30%. Therefore, novel therapeutic approaches are urgently needed for older PCNSL patients. Recently, nivolumab, an anti-PD1 antibody, showed promising clinical activities in relapsed/refractory PCNSL, and we hypothesized that addition of nivolumab in the frontline setting would be safe and improve survival outcomes of older PCNSL patients who are deemed poor candidates for ASCT or WBI. Methods: In this phase 1/1B single-arm multicenter study, patients ≥ 65, who were deemed poor candidates for ASCT and WBI, with previously untreated PCNSL received at least 3 cycles of HD-MTX-containing chemotherapy followed by nivolumab consolidation for 6 cycles (NCT 04022980). Patients with systemic lymphoma or known ocular involvement were excluded from the study. Stage 1 was designed to evaluate the safety of nivolumab consolidation after HD-MTX-containing induction chemotherapy. A 3+3 design was used as safety run-in, initiating 6 patients on nivolumab at the FDA-approved single-agent dose and monitoring for dose-limiting toxicities (DLTs) during Cycle 1. If less than 2 out of 6 subjects experienced a DLT, then the stage 2 part of study would initiate to evaluate the efficacy of nivolumab consolidation in terms of the 2-year PFS. The patient's neurological function was assessed at baseline and throughout the study follow-up using the Neurologic Assessment in Neuro-Oncology (NANO) scale. Results: A total of 14 patients enrolled in the study between April 2020 and December 2022 at 4 US sites. In 14 evaluable patients who underwent the study treatment, the median age was 72 years (range, 65-79), 71% patients were female, and 35% patients had ECOG score of 2 or 3. Variations of the following regimens were used for induction: 43% R-MPV (rituximab, methotrexate, procarbazine, and vincristine) (43%), 29% MRT (methotrexate, rituximab, and temozolomide), 21% MR (methotrexate and rituximab), and 7% MATRix (methotrexate, cytarabine, thiotepa, and rituximab). After induction, 58% achieved a complete response (CR), 33% achieved a partial response (PR), and 8% had a stable disease (SD). Patients received a median of 6 cycles of nivolumab consolidation. Patients who received at least 1 cycle of nivolumab consolidation achieved an overall response rate of 83% with a CR rate of 75%. With a median follow-up duration of 18 months, the 1-year overall survival (OS) and PFS rates were 91.7% and 66.1%, respectively. No DLTs were observed during Cycle 1 of nivolumab consolidation in Stage 1. The most common grade ≥ 3 Adverse Events (AEs) associated with nivolumab consolidation included neutropenia (14%) and fatigue (7%). One patient (7%) developed a grade 4 Stevens-Johnson syndrome associated with sepsis and acute kidney injury, requiring discontinuation of nivolumab after Cycle 1. Conclusion: The current study demonstrates encouraging safety and clinical outcomes of nivolumab consolidation in older PCNSL patients who are deemed poor candidates for ASCT or WBI. No DLT was observed during the safety run-in phase, and there was no unexpected toxicity associated with nivolumab although 1 patient discontinued the study treatment due to Stevens-Johnson syndrome, a rare but known AE associated with nivolumab, after Cycle 1. Overall, nivolumab consolidation was associated with favorable survival rates in a group of patients with poor-risk PCNSL. We are in the process of identifying various clinical and biological factors, including 9p24.1 copy number alteration, in association with the response to nivolumab consolidation. Furthermore, changes in the neurological function based on the NANO scale assessed before and after the nivolumab consolidation are being analyzed.

Axicabtagene ciloleucel as second-line therapy in large B cell lymphoma ineligible for autologous stem cell transplantation: a phase 2 trial

Axicabtagene ciloleucel (axi-cel) demonstrated superior efficacy compared to standard of care as second-line therapy in patients with high-risk relapsed/refractory (R/R) large B cell lymphoma (LBCL) considered eligible for autologous stem cell transplantation (ASCT); however, in clinical practice, roughly half of patients with R/R LBCL are deemed unsuitable candidates for ASCT. The efficacy of axi-cel remains to be ascertained in transplant-ineligible patients. ALYCANTE, an open-label, phase 2 study, evaluated axi-cel as a second-line therapy in 62 patients with R/R LBCL who were considered ineligible for ASCT. The primary end point was investigator-assessed complete metabolic response at 3 months from the axi-cel infusion. Key secondary end points included progression-free survival, overall survival and safety. The study met its primary end point with a complete metabolic response of 71.0% (95% confidence interval, 58.1–81.8%) at 3 months. With a median follow-up of 12.0 months (range, 2.1–17.9), median progression-free survival was 11.8 months (95% confidence interval, 8.4–not reached) and overall survival was not reached. There was no unexpected toxicity. Grade 3–4 cytokine release syndrome and neurologic events occurred in 8.1% and 14.5% of patients, respectively. These results support axi-cel as second-line therapy in patients with R/R LBCL ineligible for ASCT. ClinicalTrials.gov Identifier: NCT04531046.

Retrospective Evaluation of Real-World Treatment Patterns in Patients with Mantle Cell Lymphoma - REALM in a Single Brazilian Center

Introduction Epidemiological data in Brazil about Mantle Cell Lymphoma (MCL) are scarce. Recently, we could observe improvement in survival outcomes with the inclusion of rituximab maintenance in therapy schemes, use of proteasome inhibitors and Bruton's tyrosine kinase inhibitors (BTKi). Considering this, there is a need to understand real world patterns, barriers, treatments, and outcomes among Brazilian MCL patients. Thus, the aim of this study is to evaluate clinical parameters, outcomes considering clinical profile, types of treatments, rate of Autologous Stem Cell Transplantation (ASCT) as consolidation strategy, as well as to evaluate the survival of refractory/relapsed (R/R) patients in the pre BTKi era. Methods This is an observational retrospective cohort study of consecutive patients in a single institution (HEMOMED) from January 2009 to December 2020. Inclusion criteria: Adult male or female patients ≥ 18 years of age and MCL diagnosis. Exclusion criteria: enrolment in studies that prohibit any participation in this Observational Study. Results Forty-seven patients were enrolled, 38 (80.9%) were male patients. Median age was 65 (35-84) years old and 20 (42.6%) were retired workers. From 42 patients with available data, 28/42 (66.6%) presented ECOG > 1 and 37/42 (88%) advanced disease. In 30 patients with available data, 20/30(66.6%) had high risk MIPI. Three of 47 patients (6.3%) had indolent presentation and watchful waiting was considered, however all three patients required treatment - median time to treatment 23.4 (95IC 5.9 - 27.7) months and 1/47 (2.1%) patient was considered for exclusive palliative regimen. Thus, in 43 patients, 16 (37.2%) were considered candidates for ASCT in diagnosis. The first-line treatment were: RCHOP 17/43 (39.5%), R-DHAP/R-DHAOX 9/43(20.9%), R-HyperCVAD 4/43 (9.3%) and BR 4/43 (9.3%). Complete Response and overall response (OR) were: 28/43 (65.1%) and 32/44(74.4%), respectively. Sixteen/43 (37.2%) received rituximab maintenance. Only 9(56.2%) of 16 candidates were submitted to ASCT consolidation, seven patients that were not submitted to ASCT: 2 did not achieve OR after induction, 1 died due to COVID-19 after C2 RDHAOX, 1 refused due to the risk of COVID-19, 1 was not submitted by another ASCT team due to Partial Response, 1 was not submitted due to delay and 1 presented stem cell mobilization failure after R HyperCVAD. The three-year OS and PFS were 60% and 44%, respectively. Median overall survival (OS) and progression-free survival (PFS) were 39.5 (95CI 33.9 - 45.1) and 28.5 (95CI 17.6-39.3) months, respectively. Patients with OR after first-line treatment presented better OS: 67.9 (95CI 40.6-95.3) compared to patients with stable disease or progression 19.4 (95IC 18-20.8) months, p < 0.01. In addition, in the group with OR, rituximab maintenance significantly improved median PFS: 38.23 (95CI 32.39- 44) compared to 31.4 (95IC 9.5- 44) months, p=0.039. (FIGURE A) Patients that received ASCT compared to the ones that were not submitted to ASCT presented 3 years OS of 78% compared to 59%, respectively. In this, group, median OS was not reached compared to other patients with median of 38.2 (95CI 28.6-47.9) months, p=0.06 (FIGURE B). Twenty-two R/R MCL patients were studied. Ten/22 (45.4%) presented early progression disease (POD24). Cytarabine regimen was the most frequently used 6/22(27.2%) with 3/22 patients (13.4%) receiving bendamustine. OR was achieved in 6/22 (27.2%) patients. Allogeneic ASCT was used in 2 patients. The three-year OS and PFS after R/R were: 29% and 11%, respectively. Median OS and PFS were 23.2 (95CI 8.4 - 37.9) and 6.9 (95CI 3.1-10.6) months, respectively. Discussion It is possible to observe in this small cohort that the majority of patients present high risk MIPI, with only 56.2% of candidates submitted to ASCT consolidation. It was also possible to observe the impact of COVID-19 in these patients. OR after first-line treatment was related to a good prognosis. The inclusion of rituximab in the last years, as maintenance therapy after first-line treatment in patients with OR, improved PFS. Moreover, it is important to highlight that the approval of mandatory reimbursement for BTKis in R/R MCL for the private sector by Agência Nacional de Saúde Suplementar (ANS) in Brazil occurred on February 2021, so our data for R/R MCL showed poor prognosis, like already indicated by other published retrospective data in the pre BTKi era. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Quadruplet Induction, Autologous Transplantation and Minimal Residual Disease Adapted Consolidation and Treatment Cessation in Older Adults ≥70y with Newly Diagnosed Multiple Myeloma: A Subgroup Analysis of the Master Trial

Background: Half of adults with newly diagnosed multiple myeloma (NDMM) in the US are ≥70y. This age group is often considered ineligible for intensive therapy and not routinely included in prospective clinical trials. The phase II MASTER trial (NCT03224507) for NDMM did not have an upper age limit as eligibility and showed high rates of minimal residual disease- (MRD) negativity among NDMM patients receiving quadruplet induction, autologous stem cell transplantation (ASCT) and response-adapted consolidation therapy (Costa LJ et al JCO 2021). Here, we conducted a post-hoc analysis comparing the outcomes of patients age ≥70y. vs <70y. Methods: The MASTER trial enrolled patients with NDMM, with ECOG ≤2, measurable disease and creatinine clearance ≥40 ml/min as key eligibility criteria. Patients received Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRD based induction, ASCT and response adapted Dara-KRD consolidation. The primary end point was achievement of MRD-negativity (<10-5) at any point during follow-up by NGS (ClonoSEQ®). Secondary endpoints included achievement of MRD <10-6 at any point, rate of MRD negativity post-induction, rate of complete response, progression-free survival (PFS) and overall survival (OS). Those who achieved two consecutive MRD-negative assessments underwent treatment free observation and MRD surveillance (MRD-SURE). For the current analysis, we compared the achievement of primary and secondary endpoints using intent-to-treat principle between the study cohorts. Results: Of the 123 enrolled patients, 24 (19.5%) were ≥70y at the time of diagnosis (5 were ≥75y). Baseline characteristics were similar between the two age groups (Table 1). All 24 patients received planned ASCT. Compared to younger adults, older adults had similar rates of MRD negativity post induction (36% vs 41%; p= 0.66), but lower rates of overall MRD negativity (<10-5) (65% vs 84%; p=0.03) and lower rates of complete response (71% vs 93%; p= 0.002) (Table 1). Older and younger patients had similar probability of achieving MRD-SURE (61% vs. 74%, P=0.18). Median time on protocol treatment was 11.7 (IQR 7.7-15.2) months (m) for older patients and 11.6 (IQR 8.0-14.7) m for younger patients (p=0.85). Grade ³3 treatment emergent adverse events occurred in 79% of older and 69% of younger patients (p=0.31). No patients in the older group permanently discontinued protocol therapy due to toxicity. At a median follow up of 35.9 (range 1-51) m, older vs younger adults had similar PFS (3-y PFS 86.3% vs 80.3%; p= 0.74)(Fig) and OS (3y OS 95.8% vs 88.7%; p= 0.53). Three deaths occurred during the treatment period, of which one patient was ≥70y (unwitnessed sudden death 2 m after ASCT and before consolidation). Conclusion: Our study demonstrates that older adults can be candidates for quadruplet induction, ASCT, and MRD-adapted consolidation therapy and can derive similar benefits as younger NDMM pts. While toxicity may be higher among older adults, it does not appear to compromise treatment continuation, PFS or OS. Chronologic age, by itself, should not be an eligibility criterion from trials utilizing higher intensity therapies. Future studies should focus on how to identify older adults who can benefit from intensive frontline MRD adapted therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

EVALUATION OF BLOOD CELL COUNT USING THE SYSMEX XN-1000 AUTOMATIC HEMATOLOGY ANALYZER TO OPTIMIZE COLLECTION OF PERIPHERAL BLOOD PROGENITOR CELLS BY LEUKAPHERESIS

Autologous stem cell transplantation (ASCT) is a treatment modality for several diseases. Prediction of successful mobilization may be useful to optimize hematopoietic stem cell (HSC) collection. The objective was to identify characteristics that can influence the effectiveness of mobilization and create a model to predict the success of mobilization in candidates for ASCT. This was a retrospective study, and data from patient candidates for ASCT between 09/2015 and 12/2021 were analyzed. Participants were assisted in five hospitals and laboratory procedures were performed at the Cell Processing Center (CPC) of Cetebio/Fundação Hemominas, Brazil. The medical records of the participants were reviewed to obtain the following information: gender, age, weight, diagnosis, mobilization, mobilization cycle, number of previous chemotherapy regimens and previous radiotherapy. The laboratory data analyzed were CD34+ cell enumeration and pre-collection peripheral blood (PB) blood count. Enumeration of CD34+ cell was performed using the ISHAGE protocol. The blood count was performed using an automated counter (SYSMEX XN-1000 AS-01). The studied outcome, good mobilization, was defined as a viable CD34+ cell count ≥ 20/uL in the PB. Model derivation was performed using logistic regression. The level of classification accuracy of model was tested in a subset of participants. The study population included 807 patients, 413 (51%) of whom were male. The median age was 54 (1-74) years. Multiple myeloma was the most common diagnosis (58,2%), followed by lymphoma. Of the 807 participants, 74 failed in previous mobilization attempts, totaling 881 cycles of mobilizations and collection attempts. Of the 623 participants, 353 were good mobilizers. Increasing patient weight, lower mean corpuscular volume (MCV), higher nucleated red blood cells (nRBC), peripheral blood mononuclear cells (PBMC), and immature granulocyte count were significantly associated with good mobilization. In addition, participants diagnosed with multiple myeloma were two times more likely to be good mobilizers than patients with lymphoma (OR=1.92; 95%CI: 1.21 – 3.05; P=0.006). The model was applied to the validation set to identify patients who underwent apheresis (CD34+ cells count ≥ 10 μL), resulting in a sensibility of 69%, a specificity of 95%, positive predictive value of 98%, a negative predictive value of 50%. The results of our study are extremely relevant to institutions that do not have a flow cytometer and rely on other institutions to define HSC collection by apheresis. Cetebio serves nine transplant centers. The centers that perform the collection of HSC are located between 40 to 568 km away from Cetebio (place of quantification of CD34+ cells). Predicting the outcome of mobilization may allow the adoption of complementary measures, such as the use of plerixafor. Furthermore, it would better optimize the collection of CPH by apheresis. Thus, it would be possible to avoid additional collection days, reducing costs and risks related to administration of additional doses of G-CSF, catheter maintenance and prolonged hospital stay. Success in mobilization was greater in participants who underwent the first mobilization cycle and who had a diagnosis of multiple myeloma. Furthermore, higher weight and levels of nRBC, immature granulocytes, and PBMC, as well as lower levels of MCV, were associated with successful mobilization.

Conditioning with melphalan 200 mg/m2 and subsequent ASCT improves progression-free and overall survival in elderly myeloma patients compared to standard of care.

Despite the effectiveness of newer drugs for the treatment of multiple myeloma (MM), the outcomes are further improved by subsequent autologous stem cell transplantation (ASCT). Data on effectiveness in older patients are limited. We compared outcomes in patients aged 65-75 years depending on whether they were treated with ASCT or not and compared those to outcomes in patients <65 years. This was a retrospective, single-center study. We compared progression-free survival (PFS) and overall survival (OS) for all MM patients below and above the age of 65 years treated ± ASCT at the Karolinska University Hospital between 2010 and 2020. PFS and OS were calculated by the Kaplan-Meier method. Variables affecting PFS and OS were evaluated using Cox regression model. Both PFS and OS were improved in the group 65-75 years treated +ASCT compared to those treated pharmacologically (p=0.008 and p < 0.001, respectively). There were no significant differences between patients <65 years and those 65-75 years treated with ASCT. The findings indicate that even patients >65 years should be evaluated as candidates for ASCT. An individualized approach supported by a frailty/geriatric assessment score could assist clinicians to select the appropriate treatment for each patient.

PB2182: CHARACTERISTICS THAT INFLUENCE THE STEM CELL COLLECTION BY APHERESIS IN PATIENTS WHO ARE CANDIDATES FOR AUTOLOGOUS STEM CELL TRANSPLANTATION

Background: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a consolidation treatment for several hematologic malignancies such as multiple myeloma (MM), Hodgkin lymphoma (LH) and non-Hodgkin lymphomas (diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), NK/T- cell lymphoma (NKTL), etc.). However, between 5-40% of patients fail to obtain an adequate collection of hematopoietic progenitor cells (HPCs), this is known as mobilization failure. This failure can be due to multiple factors that may be associated with the previous treatment of the disease (number of treatment lines, type of chemotherapy or radiotherapy), the patient (age, bone marrow cellularity) or the collection procedure and other biochemical parameters like pre-count CD34+ cell/ul, pre-harvest hemoglobin and platelet count. Aims: -To determine the clinical characteristics of patients and the haracteristics of apheresis procedures in patients who had fail to obtain an adequate collection of HPCs by apheresis of peripheral blood and who are candidates for ASCT. Methods: A retrospective study was carried out, in patients aged between 18 and 65 years old, with hematological onco diseases who went to the Blood Bank of the National Cancer Institute for the collection of HPCs from peripheral blood by apheresis for ASCT, between January 2017 and December 2020. A review of the electronic medical record of each patient was carried out, as well as the records of the procedure for collecting HPCs. The nominal variables were compared by chi-square test and the quantitative variables with Student´s t-test, a value less than 0.05 was considered statistically significant. Results: The study included 127 patients, who underwent HPCs collection for ASCT; 15% (19 patients) had failure to mobilize (63% men; mean age 48 years). The most frequent diagnosis was MM 47.4%, followed by non-Hodgkin lymphoma 42.1% (37.5% DLBCL, 25% MCL, 37.5% NKTL, follicular lymphoma and peripheral T-cell lymphoma) and Hodgkin lymphoma with 10.5%. The most common used method of mobilization was chemotherapy with filgrastim (57.8%), followed by filgrastim. In the pre-harvest studies, 26% had anemia and 42% thrombocytopenia; pre-count CD34+ less than 20/ul was presented in 94%. More than 50% required two or more days for collection. During the process to obtain HPCs, the median duration of this procedure was 273 minutes (range 193 to 311 minutes), with an average processing speed of 81.1 ml/h. While the mean volume extracted was 16 879 ml (range 4 087 to 20 463ml) with an average number of complete cycles of 14.6. It was determined that age >50 years, two lines of treatment, mobilization with chemotherapy and filgrastim, pre-count CD34+ less than 20/ul and more days of harvesting were associated with HPCs harvest failure. While other factors such as sex, bone marrow status, radiotherapy site, pre-harvest hemoglobin, platelet count did not have a statistically significant association. Image:Summary/Conclusion: In our study, harvest failure (15%) is within the range reported in the literature and the factors associated with this failure have also been documented in other studies. With these data obtained, it could be established that patients at high risk of failure to harvest, such as those with multiple myeloma, are considered to be harvested receiving a smaller number of lines of treatment and consider stimulation with other stimulants such as plerixafor.

Current treatment options and considerations for patients with relapsed/refractory diffuse large B cell lymphoma in North Macedonia

Autologous stem cell transplantation (ASCT) is considered standard therapeutic approach for patients with relapsed and refractory (R/R) diffuse large B cell lymphoma (DLBCL) that are transplant eligible. For transplant ineligible patients there are few therapeutic options and novel targeted therapies and immunotherapy that are still in development. Treatment of such patients with poor prognosis is considered to be a challenge and there is constant need for new salvage treatment regimens. The aim of this study was to evaluate patients’ characteristics and treatment strategies and considerations for diffuse large B cell lymphoma in our department, and to promote new therapeutic possibilities for R/R patients with NHL DLBCL. A total of 308 patients with NHL were treated at University Clinic for hematology from 2008 until 2020 and 49% (151) of patients with NHL DLBCL were included in this study. Survival analysis of all analyzed relapsed/refractory NHL patients revealed statistically significant better survival in patients with low risk IPI score, disease stage I/II and patients with age &lt;60 years. R-CHOP was superior treatment as first line regimen and in the R/R patients, ASCT was statistically superior to other available second line treatment options. Overall survival in patients with DLBCL that achieved complete response after initial treatment was 80%. The incidence of disease relapse after initial treatment in the first 12 months was 18%. Overall survival in all treatment groups was 60% in the evaluated period of 2.5 years follow up. A total of 60% of patients with relapsed forms of NHL DLBCL were candidates for treatment with high-dose chemotherapy and ASCT. Other 40% patients were not candidates for ASCT. In conclusion we confirm the need for new treatment options for patients that relapse after ASCT and that are transplant ineligible. Patients and disease characteristics can be used to identify high-risk patients, classify once relapsed patients and define decision on further treatment.

Phase I Study of Oral Azacitidine (CC-486) Plus Salvage Chemotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Abstract Background A significant portion of diffuse large B-cell lymphoma (DLBCL) patients (35-40%) relapse or are refractory to frontline chemotherapy. The standard of care for relapsed/refractory (R/R) DLBCL patients has been salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) in eligible patients. Epigenetic alterations, such as aberrant DNA methylation patterns, have been linked to chemotherapy resistance in DLBCL. CC-486 is an oral hypomethylating inhibitor that inhibits DNA methyltransferase, and has provided evidence for chemotherapy sensitization in DLBCL (Clozel T, et al. Cancer Discovery, 2013). This provides rationale for addition of CC-486 to standard cytotoxic chemotherapy rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in R/R DLBCL patients who are candidates for ASCT. Here we report the results of the phase 1 trial investigating this combination. Methods Eligibility included age ≥ 18, a diagnosis of R/R DLBCL, follicular lymphoma grade 3B, or DLBCL transformed from indolent lymphoma who were candidates for salvage chemotherapy and ASCT consolidation. The study was conducted via standard 3+3 dose escalation of CC-486 at 200 mg (dose level (DL) 1), 300 mg (DL 2), and 150 mg (DL -1). A Dose limiting toxicity (DLT) was defined as grade ≥ 3 adverse event (AE) as defined by CTCAE v5 leading to ≥ 7 day delay in cycle (C) 1 or 2 of R-ICE chemotherapy as well as grade ≥ 2 vomiting/diarrhea, persisting 48 hours despite best supportive care. Patients received up to three 21-day cycles. CC-486 was given as a 7 day lead in prior to C1 and then on days 8-21 of C1 and C2 with doses held based on cytopenias/AE's per protocol. G-CSF was mandated with each cycle. The primary objective was to determine the recommended phase 2 dose (RP2D) of CC-486 in combination with R-ICE chemotherapy. Secondary objectives included overall response rate (ORR)/complete remission (CR) per 2014 IWG criteria, peripheral blood stem cell (PBSC) collection feasibility, and proportion of patients receiving ASCT consolidation. Biomarker objectives included assessment of locus specific and global methylation patterns in ctDNA at set time points. Results The study has completed accrual with enrollment of nine patients from two institutions, all of which completed planned therapy. Eight (89%) of the patients had relapsed &amp;lt; 1 year from completion of frontline chemotherapy. Six patients were treated at the DL1 (200 mg), three patients were treated at DL2 (300 mg), and zero patients were treated at DL-1 (150 mg) with baseline characteristics described in table 1. The most common AE's (figure 1) included nausea (78%), thrombocytopenia (78%), anemia (56%), neutropenia (55.6%), fatigue (44%), and constipation (44%). Compared with DL1, DL2 was associated with greater incidence of grade ≥ 3 hematologic AE's/cycle including neutropenia (42% v 6%), anemia (29% v 11%), and thrombocytopenia (42% v 6%); higher incidence of neutropenic fever/cycle (28.5% vs 0%); more frequent delays in day 1 of C2 or C3 of R-ICE chemotherapy (80% vs 0%); and higher rate of CC-486 doses missed in C2 and C3 due to cytopenias (40% and 4%) respectively. One DLT occurred at DL2 in a patient with grade 5 neutropenic sepsis. A planned safety review of the three patients at DL2 established that no further patients would be enrolled at this dose. No DLTs were noted in the six patients enrolled at DL1. The ORR(CR) of the 8 evaluable patients was 50%(50%) and 4/9 patients proceeded to ASCT. With a median follow up of 9.5 months (range 1.2-25.1) the median PFS and OS were 4.0 months (95% CI 2.1-NR) and 10.7 months (95% CI 9.5-NR) respectively. All 4 patients successfully collected PBSCs (defined as ≥ 3.0 x 10^6 CD34 cells/kg) with median of 4.08 x 10^6 cells/kg. Biomarker studies are pending. Discussion Patients enrolled at DL1 (200 mg) tolerated this combination well with expected hematologic AE's, no episodes of neutropenic fever, few missed doses of CC-486, no delays in R-ICE chemotherapy, and no DLTs. The CR rate was 50% and a high proportion of patients (89%) enrolled after relapsing &amp;lt; 1 year from completion of frontline therapy. Biomarker studies may provide information regarding DLBCL populations likely to benefit from combinations of chemotherapy and epigenetic priming. Biomarker studies related to locus specific and global methylation patterns in ctDNA will be presented at the ASH conference. Figure 1 Figure 1. Disclosures Hess: BMS: Speakers Bureau; ADC Therapeutics: Consultancy. Cerchietti: Celgene: Research Funding; Bristol Myers Squibb: Research Funding. Hill: Eli Lilly and Company: Ended employment in the past 24 months.

Stem Cell Collection with Daratumumab (DARA)-Based Regimens in Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM) Patients (pts) in the Griffin and Master Studies

Stem Cell Collection with Daratumumab (DARA)-Based Regimens in Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM) Patients (pts) in the Griffin and Master Studies

Pembrolizumab (Keytruda)

&#x0D; CADTH recommends that Keytruda should be reimbursed by public drug plans for the treatment of adult and pediatric patients with refractory or relapsed classical Hodgkin lymphoma (cHL) if certain conditions are met.&#x0D; Keytruda should only be reimbursed to treat patients who have failed autologous stem cell transplant (ASCT) or who are not candidates for multi-agent salvage chemotherapy and ASCT.&#x0D; Keytruda should only be reimbursed as monotherapy and if the cost of pembrolizumab is reduced.&#x0D; &#x0D;

Advances in Immunotherapy for Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease that is normally treated with combination chemotherapy combined with the anti-CD20 monoclonal antibody rituximab. Although about two-thirds of patients are cured with initial chemo-immunotherapy, a sizable minority of patients will have relapsed or refractory (r/r) DLBCL. Standard therapy for r/r DLBCL is salvage chemotherapy followed by autologous stem cell transplantation (ASCT); however, a minority of patients have long-term remission with this approach. In recent years, there has been a proliferation of immunotherapies for the treatment of DLBCL that have expanded our treatment options for these patients, providing the opportunity for durable remissions that were not previously possible. In this review, we discuss these novel immunotherapies, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies and chimeric antigen receptor (CAR) T cells. The plethora of novel agents leaves patients with more therapeutic options, but leaves the practitioner faced with challenging decisions regarding the timing and indications for use of these immunotherapies. Although studies are ongoing, no agents have been verified as alternatives to standard salvage therapy followed by ASCT at first relapse. The opportunity for durable response and broad age range eligibility makes a strong case for CAR T cells to be used as third-line therapy. The remainder of the agents discussed can be useful in specific clinical scenarios including in patients who are not candidates for ASCT or CAR T cells, as bridging therapy to CAR T cells, or in the r/r setting after CAR T cell therapy failure.

Outcomes of Autologous Stem Cell Transplantation in Very Elderly Patients with Multiple Myeloma

Outcomes of Autologous Stem Cell Transplantation in Very Elderly Patients with Multiple Myeloma

A Pilot Study of Acalabrutinib with Bendamustine/Rituximab Followed By Cytarabine/Rituximab (R-ABC) for Untreated Mantle Cell Lymphoma

A Pilot Study of Acalabrutinib with Bendamustine/Rituximab Followed By Cytarabine/Rituximab (R-ABC) for Untreated Mantle Cell Lymphoma

Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting. Karyopharm Therapeutics Inc.

Lenalidomide plus R-GDP (R2-GDP) in relapsed/refractory diffuse large B-cell lymphoma: Final results of the R2-GDP-GOTEL trial.

8019 Background: Lenalidomide is an immunomodulatory drug that could reverse rituximab refractoriness in lymphoma patients (pts). We conducted an open label multicenter phase 2 trial testing the efficacy and toxicity of a combination of lenalidomide and rituximab (R2) plus GDP schedule (R2-GDP) in Relapsed/Refractory Diffuse Large B Cell Lymphoma (R/R DLBCL) pts, not suitable for autologous stem cell transplant (ASCT). Methods: Patients with R/R DLBCL previously treated with at least 1 prior line of immunochemotherapy including rituximab, and not candidates for ASCT, were eligible. After a run-in phase period, treatment consisted of an induction phase with lenalidomide (LEN) 10 mg po d1-14, rituximab 375 mg/m2 iv d1, cisplatin 60 mg/m2 iv d1, gemcitabine 750 mg/m2 iv d1 and d8 and dexamethasone 20 mg d1-3, up to a maximum of 6 cycles. Pts without disease progression (DP) entered into a maintenance phase with LEN 10 mg, or last LEN dose received in the induction phase, d1-21 in cycles every 28 days. Primary endpoint was overall response rate (ORR) by investigator assessment. Secondary endpoints included disease free survival (DFS), event free survival (EFS), overall survival (OS), safety and response by cell of origin (COO), type of DLBCL (double-triple hit) and other microenvironment and genomic biomarkers. Results: 79 pts were enrolled between April 2015 and September 2018. Median age was 70 years (range 23-86), 48,7% women. 78 pts were considered for efficacy and safety in the intention to treat (ITT) analysis. With a median follow-up of 13 months at the time of cut-off (November 2019), ORRwas 59.0%, with 32.1% complete responses (CR) and 26.9% partial responses (PR). In the primary refractory population (n = 33), ORR was 45.5%, with 21.2% CR and 24.3% PR. There were no statistically significant differences in ORR with respect to COO. In Double-Hit R/R DLBCL (n = 16), ORR was 37.5% with 25% CR. Median OS was 12.0 months (6.9-17.0). Most common grade 3/4 (G3/4) adverse events were thrombocytopenia (60.2%), neutropenia (60.2%) and anemia (26.9%). Febrile neutropenia occurred in 14.1% pts. Most frequent non-hematologic G3/4 events were asthenia (19.2%), infection (15.3%) and renal insufficiency (6.4%). There were 4 toxic deaths related to the R2-GDP schedule. Conclusions: LEN with Rituximab and GDP (R2-GDP) is feasible and active in R/R DLBCL. Results in the primary refractory DLBCL population are particularly promising. Analysis of COO did not revealed differences in response rates. Immune biomarkers results will be showed at the meeting. Clinical trial information: EudraCT 2014-001620-29 .

Unequal Outcomes in Transplant Eligible Patients with Multiple Myeloma in Latin America: Differences between Public and Private Centers

Background Multiple myeloma (MM) is a frequent hematologic malignancy. The current gold standard frontline strategy includes a proteasome inhibitor (PI)-based induction, followed by autologous stem cell transplant (ASCT). Access to novel drugs in Latin America (LA) is limited. ASCT is available in most countries, but real access to it is highly heterogeneous. Data regarding patients´ outcomes in candidates to ASCT in the region is scarce. The aim of this study was to describe clinical characteristics and outcomes of MM transplant eligible patients in LA countries. Material and Methods Retrospective international multicenter cohort study. Consecutive MM transplant- eligible patients diagnosed between 2010 and 2018 from participating centers in Chile, Argentina, Ecuador, Mexico, Colombia, and Uruguay were included. Data were collected from clinical records in a standardized report form. We analyzed clinical characteristics at diagnosis and frontline therapy outcomes, including ASCT. Transplant-eligible patients were defined as fit patients younger than 66 years old. Active MM and response to treatment were defined according to current IMWG criteria. Inclusion criteria: 1.- Patients with newly diagnosed active MM between 2010 and 2018. 2.- Older than 18 years, and younger than 66 years. 3- Candidates for ASCT according to the evaluation of the attending physician Exclusion criteria: 1- Lack of minimum data in the clinical history 2- Plasma cell leukemia, AL amyloidosis or solitary plasmacytoma. 3- HIV infection 4-No consent and/or Ethics Committee approvals. Statistical analysis A descriptive statistic has been done. Comparisons of characteristics between groups was made usingT-student, Chi2 or ANOVA, as appropriate. Survival analysis was performed using Kaplan-Meier curves. Comparisons of survival between groups were made by the logarithmic recording method and the calculations of the risk relationships by Cox regression. Statistical analysis was performed by using STATA 13. Results We included 1293 patients in the study, 363 from Chile, 395 from Argentina, 209 from Colombia, 45 from Ecuador, 151 from Mexico, and 130 from Uruguay. The main characteristics at diagnosis and therapeutic strategies are shown in Table 1. Optimal response (sCR, CR and VGPR) was achieved in 38% of the patients in the cyclophosphamide, bortezomib, and dexamethasone (CyBorD) group, in 46% in the bortezomib, thalidomide, and dexamethasone (VTD) group, and in 36% in the cyclophosphamide, thalidomide, and dexamethasone (CTD) group, the 3 main induction regimens used. Only 53% of patients finally received ASCT. Significant differences were found between both groups, private and public institutions, regarding burden of symptoms, ISS staging, access to PI based induction, ASCT completion and adequate maintenance, with patients from the latter being more symptomatic, and receiving suboptimal therapy. FISH analysis was performed in less than 50% of patients, both in the public and private setting. With a median follow up of 34 months (range 1-113), median overall survival (OS) was 86 months. The 5-year progression free survival (PFS) was 38% and 5- year overall survival (OS) was 64%. When comparing public vs private settings, 5 year OS was 45% vs 80%, with a median OS of 56 months vs not reached, respectively (P&lt;0,0001). In the multivariable analysis renal failure (p=0.03), achieving less than VGPR response (p&lt;0.0001), not undergoing ASCT (p=0.001), and not receiving maintenance (p=0.005) were independent factors associated with worse outcome. Conclusion This is the largest report on transplant eligible patients with MM in LA. Great inequities are shown between public and private health systems. Survival in transplant-eligible patients is lower than that described in other regions. Only one third of patients had FISH performed. This means that very few patients are treated with a risk-based induction in LA. Patients in the public setting are diagnosed with a more symptomatic disease, probably due to a late diagnosis. OS is significantly worse in the public setting. This might be explained by the significant differences in access to PI-based induction, ASCT and maintenance between private and public institutions, with patients from the latter receiving suboptimal frontline therapy and maintenance. Reasons for 47% of potential candidates not being transplanted merit further analysis. Table 1 Disclosures Peña: Novartis: Other: Congress inscription and flights; Tecnofarma: Other: Congress inscription and flights; Roche: Other: Congress inscription and flights; Biotoscana: Other: Congress inscription and flights; Janssen: Other: Congress inscription and flights; Pfizer: Membership on an entity's Board of Directors or advisory committees. Rojas:Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfeizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Abello:Takeda: Other: Participation in advisory board meeting. Gomez-Almaguer:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

Outcome of Autologous Stem Cell Transplantation Following PD-(L)1 Based Salvage Therapy for Multiply Relapsed Patients with Classic Hodgkin Lymphoma

Outcome of Autologous Stem Cell Transplantation Following PD-(L)1 Based Salvage Therapy for Multiply Relapsed Patients with Classic Hodgkin Lymphoma