Post Stem Cell Transplantation Research Articles

Effect of maintenance therapy (MT) on real-world outcomes (RWO) of patients (pts) with newly diagnosed multiple myeloma (NDMM) post stem cell transplant (SCT).

7562 Background: SCT followed by MT is the standard of care for pts with transplant-eligible (TE) NDMM. Five randomized clinical trials (RCTs) comparing lenalidomide MT versus no MT showed improved progression free survival (PFS), but no overall survival (OS) benefit except for one by McCarthy et al. that allowed pt crossover between treatment arms. Use of MT has also been associated with an increased risk of second primary malignancies and an inferior quality of life. We report RWO post SCT with and without MT in TE NDMM. Methods: We performed a multi-center, retrospective, observational study using the de-identified COTA real-world database derived from the EMRs of US centers. Pts with NDMM from 1/1/2012 to 1/1/23 were included in the study. Kaplan-Meier method was used to evaluate time to next treatment (TTNT), OS, follow-up time (reverse OS endpoint), and report log-rank test p-values. TTNT was defined in two ways: time from SCT to the earliest of initiation of next line of therapy (LOT) or death (TTNT1) and the time from 2nd LOT post-SCT to the earliest of initiation of next LOT or death (TTNT2). A propensity score (PS) matched analysis was used to compare study cohorts and report hazard ratios (HRs) using the Cox proportional hazards method. High risk cytogenetic abnormalities (HRCA) were defined as pts with 17p(-), t(4;14), t(14;16), t(14;20) and 1q+. Results: 1928 ptsmet the study criteria: 957 pts received SCT with MT (M) and 971 pts received no MT (NM). Median age at Dx was 61 y, 57% were male, 70% were White, and 31.2% had HRCA with a median follow-up of 64 months (mos) (95% CI: 61.6, 66.7). In the M vs NM arms, 29.6% and 32.7% pts had HRCA, respectively. Median TTNT1 for M vs NM was 51 vs 36 months (mos), (p<0.001), respectively. Median TTNT2 for M vs NM was 11.7 vs 21.6 mos, (p<0.001), respectively. Median OS for M vs NM was 108.8 mos vs 126.3 mos, (p=0.08), respectively. In the PS model, the NM group had significantly lower hazard of TTNT2 and OS events (HRs 0.65 and 0.85, p<0.001 and p=0.08, respectively). Conclusions: Our study demonstrates improved TTNT2 outcomes with the NM approach. M therapy did not have an impact on OS in this cohort. Both results indicate an absence of long-term benefit with the use of M therapy. OS is a difficult primary outcome to achieve in MM RCTs where survival may have to be collected for decades. Thus, our large study of RWO with long-term follow-up is valuable. [Table: see text]

Pediatric acute myeloid leukemia with t(8;21) and KIT mutation treatment with avapritinib post-stem cell transplantation: a report of four cases.

Acute myeloid leukemia (AML) with t(8;21) (q22;q22), which forms RUNX1::RUNX1T1 fusion gene, is classified as a favorable-risk group. However, the presence of mutations in KIT exon 17 results in an adverse prognosis in this group. Avapritinib, a novel tyrosine kinase inhibitor, was designed to target KIT mutation. We report a retrospective study of four pediatric patients with AML with t(8:21) and KIT exon 17 mutation who were treated with avapritinib, three of them failed to demethylate drugs and donor lymphocyte infusion targeting RUNX1::RUNX1T1-positivity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, all patients with RUNX1::RUNX1T1 positivity had turned negative after 1, 9, 7, 2 months of avapritinib treatment. The common adverse effect of avapritinib is neutropenia, which is well-tolerated. This case series indicates that avapritinib may be effective and safe for preemptive treatment of children with AML with t(8;21) and KIT mutation after allo-HSCT, providing a treatment option for preventing relapse after allo-HSCT.

Posterior reversible encephalopathy syndrome post stem cell transplantation in sickle cell disease: case series and literature review.

Posterior reversible encephalopathy syndrome (PRES) is a serious neurological syndrome that may develop following immunosuppressive therapy for stem cell transplantation (SCT). We report 8 patients with sickle cell disease (SCD) who developed PRES, which is likely to be related to immunosuppression. This is retrospective cohort analysis of the SCD registry at the King Faisal Specialist Hospital and Research Center (KFSHRC) in Riyadh, Saudi Arabia. Inclusion criteria included all adults SCD patients who underwent SCT from 2011 until 2022. We explored all cases of PRES in patients with SCT. PRES was diagnosed with MRI imaging showing reversible vasogenic cerebral edema associated with neurological symptoms including severe headache, seizures, encephalopathy, delirium, and visual disturbances. During ten years follow-up (2011-2022) we found 8 patients with PRES (age range between 14 to 37 years at diagnosis) PRES occurred 8 to 124 days following SCT in 7 cases and one patient developed PRES 8 months prior to SCT. All patients were on immunosuppressive medications, including tacrolimus, cyclosporine, sirolimus and or mycophenolate mofetil. Headache, seizures, visual hallucinations, confusion, and drowsiness were the most common presenting symptoms. MRI showed abnormalities in the occipital, parietal and frontal lobes in most cases. Recovery was complete in all patients and no recurrences were noted. Two patients had graft versus host disease (GVHD). We compared risk factors for PRES among the 8 cases and 136 SCT in SCD patients who did not develop PRES. There was a significant association between PRES and imaging abnormalities, including previous bi-hemispheric infarctions (p = 0.001), and cerebral microbleeds (CBMs). PRES was strongly associated with presence (p = 0.006), size (p = 0.016) and number (p = 0.005) of CMBs. PRES can develop days to weeks following SCT in patients with SCD, and is associated with immunosuppressive therapy, previous bi-hemispheric infarctions and CMB. Prompt recognition and intervention leads to good recovery.

Lenalidomide‐induced posterior reversible encephalopathy syndrome: A case report

AbstractPosterior reversible encephalopathy syndrome (PRES) is a disorder of cerebrovascular dysregulation. To our knowledge, we present the first case of lenalidomide‐induced PRES in English. A 59‐year‐old woman with history of multiple myeloma status post stem cell transplant and induction triple therapy 6 months ago with partial remission and subsequent high‐dose melphalan 1 month ago presented with progressive vision loss for 1 week. Her systolic blood pressure was >180 mmHg, and neurological examination demonstrated decreased vision bilaterally. Brain MRI revealed significant T2 hyperintensity restricted to temporal and occipital lobes and left occipital parenchymal hemorrhage and diffuse leptomeningeal enhancement. She had a witnessed generalized tonic–clonic seizure and EEG that captured an electrographic seizure originating from the occipital lobe. Her vision improved rapidly after discontinuing the lenalidomide. She was discharged to rehab with a normal neurological examination. We report the first English case of presumed lenalidomide induced PRES in a patient undergoing multiple myeloma treatment.

Post-stem cell transplant maintenance in FLT3mut acute myeloid leukemia - A retrospective analysis: Outcomes are improved with midostaurin but not with gilteritinib.

Post-stem cell transplant maintenance in FLT3mut acute myeloid leukemia - A retrospective analysis: Outcomes are improved with midostaurin but not with gilteritinib.

Ixazomib Maintenance Therapy in Chinese Patients with Newly Diagnosed Multiple Myeloma Not Treated with Stem Cell Transplantation: A Single-Arm, Open-Label Study

Introduction: Multiple myeloma (MM) is a life-threatening cancer of plasma cells in the bone marrow. It often leads to bone marrow failure and bone destruction. Lenalidomide is the only drug approved by Food and Drug Administration (FDA) and European Medical Association (EMA) as maintenance therapy for MM post stem cell transplantation (SCT), however it is not approved as maintenance for patients who are ineligible for high-dose therapy followed by SCT and is also not suitable for all patients due to toxicity and new primary malignancy (NPM) concerns. Hence, new maintenance agents are needed to offer patients continuous disease control while maintaining their health-related quality of life (HRQoL). Ixazomib, an oral protease inhibitor, was approved by FDA for MM patients with at least one prior therapy. The present study assessed the long-term safety, tolerability and efficacy of ixazomib maintenance therapy in Chinese newly diagnosed MM (NDMM) patients who had not undergone SCT. Methods: The C16021 CCS (NCT03748953) was a single arm, open-label extension of the TOURMALINE-MM4 (NCT02312258) phase 3 clinical trial, and was conducted from June 2018 to October 2022. It included Chinese patients aged ≥18 years with a confirmed diagnosis of symptomatic NDMM who had achieved a major response [complete response (CR), very good partial response (VGPR), or partial response (PR)] with initial MM therapy. Patients received oral ixazomib capsules at days 1, 8, and 15 of every 28-day cycle. The dose of ixazomib was escalated from 3 mg to 4 mg if it was tolerated during the first 4 cycles. The duration of treatment was approximately 24 months or until patients experienced progressive disease (PD) or unacceptable toxicity, whichever occurred first. The primary objective was to assess long-term safety and tolerability of ixazomib. The secondary endpoints included progression free survival (PFS), overall survival (OS), time to progression (TTP), time to next line therapy (TTNT), incidence of new primary malignancy (NPM) and HRQoL. Results: A total of 37 patients were included in the study from 7 study centers in China. Of these 37 patients, 35 patients were included in the safety analysis. The dose was escalated to 4 mg at day 1 of cycle 5 in 77% of patients. A total of 34 patients (97%) experienced at least 1 treatment emergent adverse events (TEAE) with 30 patients (86%) experiencing a treatment-related TEAE and 16 patients (46%) experienced a Grade ≥3 TEAE. The most common Grade ≥3 TEAEs reported were thrombocytopenia (2 patients, 6%) and pneumonia (2 patients, 6%). No NPMs were reported. SAEs were reported in 7 patients (20%) and 2 patients (6%) had their study drug discontinued permanently due to a TEAE. Three patients (9%) experienced TEAEs of peripheral neuropathy (PN, all grade 1 or 2) and all 3 patients had resolution and improvement of PN events during the treatment period. The median time to resolution of PN events was 24.0 days and median time to improvement of PN events was 8.0 days. Overall, 33 patients were included in the efficacy analysis. The median age was 68.3 years, male 64% and female 36%, ISS stage at initial diagnosis was 21%, 30% and 48% for stage I, II and III, respectively. The median time from initiation of induction therapy to first dose of study drug was 8.9 months. With a median follow-up of 15.9 months, median PFS and TTNT were 21.3 months and 24.7 months, respectively. If counting from induction therapy, median PFS was 30.0 months. All patients were still alive at date of last contact. Three patients (9%) demonstrated deepening of response during treatment. Of note, since only 9 patients (27%) had VGPR or PR at study entry, the potential for assessing deepening of response in this study was limited to these 9 patients. Ixazomib maintenance treatment showed no negative impact on HRQoL, as measured by the EORTC QLQ-C30, EORTC QLQ-MY20, EQ-5D-5L, and EQ VAS. Conclusion: Ixazomib maintenance therapy showed a tolerable safety profile with prolonged PFS in Chinese patients and the response was maintained thus providing a valuable treatment option in NDMM patients who have not undergone SCT. The results of this study were consistent with TOURMALINE-MM4 global study.

Upfront Radiation Therapy (RT) for Post-Stem Cell Transplant Multiple Myeloma (MM) Patients with Oligo-Relapse/Progressive Disease: Factors Associated with Favorable Outcomes

Introduction: Relapsed or refractory disease post-stem cell transplant (SCT) for Multiple Myeloma (MM) can be clinically challenging. For localized relapses, radiation therapy (RT) can represent an attractive treatment modality. However, data on outcomes with RT remains scarce. We investigated the impact of RT as a treatment modality in the setting of oligo-relapse and oligo-progressive plasmacytomas after SCT and explored prognostic factors associated with favorable long-term outcome Methods: In this single-institution retrospective analysis, we identified 31 MM patients who underwent upfront RT for oligo-relapse or oligo-progressive MM after SCT between 2000 and 2021. Patients were excluded if they had received systemic therapy for evidence of concurrent biochemical relapse prior to RT start. The treatment responses to stem cell transplantation (SCT) and RT were assessed following the response criteria established by the International Myeloma Working Group (IMWG), which includes the categories: complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD) and progressive disease (PD). Additionally, we utilized the R-ISS staging system to classify patients into Standard-Risk (R-ISS I), Intermediate-Risk (R-ISS II), and High-Risk (R-ISS III) groups, to allow for a comprehensive evaluation of treatment efficacy and outcomes. Results: Disease and treatment characteristics for the cohort are summarized inFigure 1. Of the 27 patients with imaging available prior to SCT, 67% (18) were assessed with PET, 22% (6) with skeletal survey, 3.7% (1) with MRI/CT, 3.7% with CT, and 3.7% (1) with x-ray. Following SCT, 48% (13) of patients were noted to have radiographic progression, 23% (7) had sCR, 23% (7) had a CR, 10% had a serologic CR, and 45% (14) had a VGPR. Among the 18 patients with radiographic evaluation (in addition to bone marrow biopsy and/or labs) post-SCT, 67% (12) were in radiographic CR at time of re-staging. Median times from SCT to new site of oligo-relapsed disease (20, 64.5%) and pre-existing but inactive sites of oligo-relapsed MM (4, 12.9%) were 31 months (3.2-117.5) and 9 months (3.4-15.9), respectively. Oligo-progressive MM, defined as active sites of disease both pre- and post-SCT were present in 22.6% (7) of patients. Prior to RT, 94% (29) had PET/CT imaging, with a median SUV of 4.4 (2.6-7.2) for target lesions. Solitary bone (77%) and extramedullary (23%) disease were treated to median dose of 30 Gy (8-49 Gy). At first disease response assessment post-RT, 77% (24) of which was done with PET/CT imaging , 42% (13) achieved CR. Among the 18 patients that did not achieve CR, 15 subsequently achieved CR at a median time of 7 months (1.7-44.5). A majority of patients (87%) received systemic therapy post-RT, with a median number of lines of therapy post-RT of 3 (1-17). The remaining 13% (4) of patients did not receive additional systemic therapy post-RT and did not experience progression. Median overall survival for the full cohort was 38 months (3.5-37.9). Conclusions: Utilizing modern systemic therapies in combination with post-transplant RT for patients with limited refractory or relapsed MM is a promising therapeutic approach. For those that remain refractory or relapse in a single site RT local control merits consideration supported by our report. Further investigation to identify patients at highest risk of progression and who may therefore benefit most from RT would be valuable. We plan to conduct additional analyses on the radiographic characteristics that may portend high risk disease, with the ultimate goal of developing well-defined criteria for giving RT earlier.

Impact of Ethnicity in Treatment Choice for Multiple Myeloma in the 3 First Lines of Therapy: Data from Observational Retrospective Real-World Study in the USA

Background In Multiple myeloma (MM) patient ethnic origin appears to be associated with significant disparities including access to care and treatment patterns in some western countries, including the USA (3). Aims Identify impact of ethnicity in real world setting on choice of treatment regimens and new combinations for MM in 1st line and relapsed/refractory (R/R) setting among patients (pts) treated recently in the USA. Methods A total of 1,209 anonymous patient charts were reported by onco-hematologists in the USA, in 2022 - 2023. The analysis focused on first 3 lines of therapy for MM: 397 first line (1L) pts, 89 receiving induction treatment prior to autologous stem cell transplantation (SCT), 101 receiving maintenance therapy after SCT and 207 pts non eligible for intensive treatment, + 457 second line (2L) and 355 third line (3L) pts. D= daratumumab; V=bortezomib; T=thalidomide; d= dexamethasone; R=lenalidomide; M= melphalan; p= prednisone; K=carfilzomib Results 39% of pts were female and 61% were male. 49% were white/Caucasians vs. non-white race, (9% Asians, 25% black/African Americans, 15% Hispanic/Latinos and 2% American Indians/native Hawaiians/other pacific islanders). In 1st line induction prior to SCT, the most frequently used regimens were VRd (33 pts), D-VRd (17 pts) and DRd (6 pts), in line with NCCN and IMWG clinical practice guidelines. Black/African Americans and Hispanic/Latinos were underrepresented in the D-VRd group, with these 2 groups corresponding 6% of pts as compared to 88% for white/Caucasian pts. No significant discrepancy in the VRd and DRd groups among different ethnic origins. In 1st line maintenance post SCT, treatment with R alone or Rd were the most frequently used (44 and 13 pts, respectively), with no difference between different ethnic subgroups. In 1st line non SCT eligible pts, the 3 major regimens used were VRd (73 pts), DRd (38 pts) and D-VRd (15 pts) and in accordance with international IMWG guidelines, except for D-VRd which is not yet recommended for this subset of pts. Breakdown between different ethnic groups was in line with the sample population, except in the VRd group where black/African Americans were slightly overrepresented compared to overall population (36% vs. 25%). In the R/R setting, there was more heterogeneity and the most frequently used regimens in 2nd line treatments were DRd (35 pts), DPd (38 pts), DKd (37 pts), Dd (30 pts) and KRd (21 pts). In this subset, black/African Americans were underrepresented in the DKd group (14% of all pts vs. 56% for white and 19% for Hispanic/Latinos). Conversely, black pts more commonly received Dd combination despite this not being included in international guidelines and considered suboptimal as a second line treatment. Few pts received doublets with no anti-CD38 antibody in 2nd line, mainly Rd (14 pts) and Vd (16 pts) but no discrepancy was identified among different ethnic subgroups. In the 3rd line setting, the 3 most used combinations were DPd (21 pts), Dd (21 pts) and Kd (18 pts). Black/African Americans were overrepresented in the DPd and, in particular in the Kd group where they represented 50% of all pts. Conclusion Those results show that regimens recommended in the last NCCN and IMWG clinical practice guidelines are the most frequently used regardless patient's ethnic origin in 1st, 2nd and 3rd line MM. However, racial disparities are noted in treatment choices with lower usage of next generation combinations for black/African Americans in first line SCT eligible pts (D-VRd) and 2nd line (DKd) when compared with white/Caucasian population. Conversely, some regimens, such as Dd in 2nd line and Kd in 3rd line tend to be more regularly considered in black/African Americans even if they may be suboptimal.

Treatment Patterns and Outcomes for Patients with Newly Diagnosed Multiple Myeloma Post-Stem Cell Transplantation Who Received Lenalidomide As First Line Maintenance Therapy (PREAMBLE)

Background: For patients with newly diagnosed multiple myeloma (NDMM) who undergo autologous stem cell transplantation (ASCT), lenalidomide (LEN) maintenance is the current treatment standard in both the EU and US (Revlimid US PI 2023). However, as nearly all patients will eventually experience disease relapse, there continues to be significant interest in exploring new strategies to improve upon LEN maintenance. This analysis aimed to characterize patients receiving LEN maintenance post-ASCT, their treatment patterns, and outcomes from a multinational real-world registry. Methods: We analyzed prospectively collected data from NDMM patients post-ASCT who enrolled in the multicenter Prospective REsearch Assessment in Multiple Myeloma: An oBservationaL Evaluation (PREAMBLE) registry. Included patients received a LEN/LEN-containing regimen post-ASCT as maintenance. Key measures included baseline demographic and clinical characteristics and survival outcomes (overall survival [OS] and progression-free survival [PFS]). Results: Of 2206 patients included in the 15 March 2023 data cutoff of PREAMBLE, 668 (30.3%) were diagnosed with NDMM, 203 of whom received ASCT at 1L. After excluding patients who did not receive maintenance therapy post-ASCT (n = 83) and patients who received a maintenance therapy post-ASCT other than LEN (n = 18), 102/203 (50.2%) patients who received LEN as 1L maintenance therapy post-ASCT were included in the analysis. Of these, 75 (73.5%) patients received LEN monotherapy and 27 (26.5%) patients received LEN combination therapy, mostly including bortezomib (18/27 [66.7%]). The number of US-based patients was similar to non-US based patients (54 [52.9%] vs 48 [47.1%], respectively). Median time from diagnosis to initiation of LEN (index date) was 9.3 months, and patients were followed up for a median of 32.9 months (min-max: 0.03-67.8). Most patients (62.7%) were stage I-II at study entry. Median duration of LEN maintenance treatment was 25.0 months (min-max: 0.5-65.1 months). Overall response rate (partial response or better) to LEN index therapy was 70.6% (72/102). At last treatment record, reasons for LEN discontinuation were provided for 61 patients, comprising disease progression (n=18), toxicity (n=15), completed treatment (n=13), maximum clinical benefit (n=2), and other (n=13). In the remaining 41 patients no LEN discontinuation data were provided. Median (95% confidence interval [CI]) PFS was 33.5 (22.6-45.7) months, with the probability of PFS ranging from 87.5% at 6 months to 43.9% at 36 months (Figure). Median OS was not reached, with survival probability ranging from 99.0% at 6 months to 80.6% at 36 months. Conclusion: LEN monotherapy continues to be the main treatment strategy for patients post-ASCT in the NDMM setting with good survival probability over 36 months. However, with more than half of the patients discontinuing treatment as a result of progression/toxicity, there is a need for more effective and tolerable maintenance treatment strategies.

CD33 CAR T-Cells (CD33CART) for Children and Young Adults with Relapsed/Refractory AML: Dose-Escalation Results from a Phase I/II Multicenter Trial

Introduction: Current therapies for patients with acute myeloid leukemia (AML) push the limits of chemotherapy intensity but cure only 30% of adults and 70% of children. Recently developed antibody-based therapies and molecularly-targeted agents only modestly improve outcomes for select patient subsets. Thus, new approaches are needed. Given the success of chimeric antigen receptor (CAR) T-cell therapies for acute lymphoblastic leukemia (ALL), we developed and optimized a novel CD33 CAR T-cell (CD33CART) construct for clinical testing in a multicenter Phase I/II clinical trial in children, adolescents, and young adults (AYA) with relapsed/refractory (r/r) AML. ( Qin H, et al. JITC 2021) We report interim results following completion of the dose-escalation phase. Methods: This multicenter phase I/II clinical trial (NCT03971799) was conducted as a 3+3 dose escalation study through the Pediatric Transplantation and Cell Therapy Consortium with National Marrow Donor Program sponsorship and managed by CIBMTR CRO. Autologous CD33CART product were centrally manufactured on a ClinicMACS Prodigy® by the Biopharmaceutical Development Program at the Frederick National Laboratory for Cancer Research (NCI). Eligibility criteria were r/r AML in subjects < 35 years old with adequate organ/performance status and an identified allogeneic stem cell transplant (SCT) donor. Bone marrow assessment was used for standard morphologic evaluation and central flow cytometric minimal residual disease (MRD) quantification. All subjects received pre-CD33CART lymphodepleting chemotherapy (LD) with fludarabine (75-120 mg/m 2) and cyclophosphamide (900-1000 mg/m 2). CD33CART doses levels (DLs) were: DL1: 3 x 10 5 CD33 CAR+ T-cells/kg; DL2: 1 x 10 6/kg; DL3: 3 x 10 6/kg and DL4: 1 x 10 7/kg. Adverse event grading used CTCAE v5 with incorporation of ASTCT consensus definitions for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). Dose-limiting toxicities (DLTs) included > grade 3 CRS, > grade 3 ICANS, and persistent > grade 3 non-hematologic toxicity that did not resolve < grade 2 in 72 hours. CD33CART persistence was assessed via flow cytometric evaluation of the blood and bone marrow. Data cut-off was June 1, 2023. Results: A total of 24 subjects (median age of 16 years, range 1-34 years), were enrolled, 12 (50%) of whom underwent a prior SCT. CD33CART products were successfully manufactured for 23 subjects and infused into 19. In 4 non-infused subjects with manufactured products, 1 died from progressive disease (PD) prior to LD, 2 transitioned to palliative care and 1 withdrew consent to seek alternative therapy. Manufacturing was not performed in one subject due to death from PD after enrollment. One morbidly obese subject (BMI=49.3) enrolled at DL4 but received treatment at DL3 due to weight-based manufacturing limitations. The median time from enrollment to infusion was 47 days (range, 24-242). (Table) Three subjects each were infused at DL1 and DL2 without DLTs. At DL3, 1 subject experienced DLT (grade 4 CRS) prompting expansion at this dose level, and no subsequent DLTs were observed. At DL4, 1 subject experienced a prolonged grade 3 CRS (> 72 hours) and grade 3 ICANS, both constituting DLT and necessitating expansion of the cohort without additional DLTs seen. Across all dose-levels, CRS was seen in 13 (68%) patients and was > grade 3 in 4 (21%) with onset typically within the first 24 hours post-infusion. Complete remission (CR) was only seen at DL4 and achieved in 2 subjects, both achieving an MRD negative CR alongside myeloid aplasia. One SCT naïve subject developed candidemia during aplasia but was able to proceed to an allogenic SCT, achieved engraftment, and was in remission at Day +100 post SCT. The second patient (post-two prior SCTs) declined third SCT, had spontaneous count recovery and remained in remission until day +119 (MRD+ relapse). Transient CD33CART expansion was detected in 9 (47.4%) subjects overall and in all 6 (100%) subjects at DL4. Conclusions: CD33CART manufacturing is feasible in children and AYAs with r/r AML with acceptable toxicity experienced in treated subjects. CD33CART expansion was best in subjects treated at DL4 (1 x 10 7/kg) with MRD negative CRs and transient myeloid aplasia occurring in 2 of 5 (40%) subjects evaluable for response (Table). Based on early clinical efficacy at DL4, enrollment continues in the phase 2 portion.

Allogeneic Stem Cell Transplantation with Myeloablative Compared with Reduced- Intensity Conditioning for AML and Mds; 20 Years Later

Background. Allogeneic stem cell transplantation (SCT) with both myeloablative (MAC) and reduced intensity conditioning (RIC) regimens is effective therapyin AML and MDS. However, the relative merits of each may differin different settings and at different time-points after SCT. We have previously reported on the role of dose intensity in a group of 112 patients with AML/MDS given SCT with different regimens between 1999 and 2004 (ASH 2004, Leukemia 2005). At that time we showed that MAC was associated with lower relapse rate, higher non-relapse mortality (NRM) and similar overall survival (OS) as RIC. MAC was associated with survival advantage in patients with active leukemia at SCT. There is paucity of data on the comparison of these 2 approaches very late after SCT (beyond 20 years). Methods. We have now updated SCT outcomes in the same cohort with a median follow up of 20 years (range, 15-22) in order to better predict long-term outcome and confirm whether late events may have changed the initial conclusions. Updated follow-up is available for all but one patient. Results. The median age at SCT was50 years (18-70). Eighty-five patients had AML and 17 had MDS (IPSS int2 or high). Fifty-eight hadactive disease at SCT (>10% marrow blasts) and 54 were inremission. The donor was HLA-matched sibling (n=58), 1-Ag mismatchedrelated (n=6) or matched-unrelated (n=48). Twenty-nine patients (26%) had poor risk cytogenetics. Forty-five patients meteligibility criteria for standard MAC and were given intravenous-busulfan (ivBu, 12.8 mg/kg) and cyclophosphamide(BuCy). Sixty-seven patients were considered non-eligible for standardMAC and were given RIC with fludarabineand ivBu (6.4 mg/kg, FB2, n=41) or reduced toxicity conditioning (RTC) with fludarabine and myeloablative dosesof ivBu (12.8 mg/kg, FB4, n=26). The medianage of RIC, RTC and MAC recipients was 57, 51 and 42 years at transplantation, respectively (p=0.001) and a larger proportion of RIC/RTC recipients had unrelateddonors (p=0.01). In all, 31 patientsare alive and 81 have died, 50 of relapse and 31 of NRM.The median age at last follow-up was 66 years (35-81). The 20-year OS rate was 29% (20-37). The rate was 40% (26-54), 19% (7-31) and 19% (7-31) after BuCy, FB4 and FB2, respectively (P=0.19). The 20-year NRM was 29% (18-45), 27% (14-51) and 27% (16-45) respectively (Figure 1, P=0.94). The 20-year relapse mortality was 31% (20-48), 54% (38-77) and 54% (40-71), respectively (Figure 2, P=0.12). Five patients with relapse in the first 5 years are very long-term survivors with no recurrent disease following additional treatments. Forty patients were alive and disease-free 5 years after SCT with a 5-year OS of 42% (33-51). Fourteen patients died beyond 5 years, 3 from late relapse (6.6 -11.8 months after SCT) and 11 due to NRM. The causes of late NRM were second malignancies (n=6), cardiovascular disease (n=3), pulmonary disease (n=1) and liver disease (n=1). The risk of late NRM was 17% (6-47), 25% (7-83) and 44% (24-81) after BuCy, FB4 and FB2, respectively (P=0.29). The risk of late NRM was 14% (4-52) and 35% (21-59) in patients younger and older than 55 years at SCT, respectively (P=0.18). Late relapse mortality was low; 6 (8-37), 13% (2-78) and 7% (1-5), respectively (P=0.81). In all, the subsequent 15-year OS in those who were alive and disease-free 5-years after SCT was 78% (59-97), 63% (29-96) and 49% (22-76), respectively. The small number of events did not allow a meaningful multivariate analysis. Conclusions. With a long-term follow-up of 20 years, RIC/RTC is an acceptable alternative to MAC in ineligible patients. NRM is lower after RIC in the early post SCT period, but late NRM negates this early advantage and at longer follow-up there is no difference between the regimens. Relapse after RIC is higher at the first 5 years after SCT. However, late relapses beyond 5 years from SCT are rare after all regimens. In all, the very long-term OS is better after MAC. However, older age at SCT for RIC may be a major cause of these observations. Longer follow up of randomized studies is needed for more definite conclusions.

Clinical and Prognostic Implications of WT1 Mutations in De Novo and Relapsed Acute Myeloid Leukemia

Introduction Wilms Tumor 1 ( WT1) is integral to cell proliferation and survival and is mutated in up to 10-15% of patients (pts) with acute myeloid leukemia (AML). WT1 mutated ( WT1 m) AML frequently co-occurs with fms-like tyrosine kinase 3 ( FLT3) and nucleophosmin 1 ( NPM1) mutations, and is generally thought to impart poorer outcomes, however the impact of WT1 m remains incompletely understood. Methods We analyzed 307 pts with WT1 m AML, identified through next generation sequencing panels of recurrently mutated myeloid genes performed at two large academic cancer centers between 2015 - 2022. Of the 307 pts, 161 (52%) had WT1 m at AML diagnosis (ND) and 146 (48%) were identified at relapse (RR). Here we describe the baseline characteristics and outcomes in pts with WT1 m AML with emphasis on co-mutated FLT3 and NPM1. Results In pts with ND WT1 m AML, the median age was 59 years (range,22-87). Pts most commonly had intermediate (41%) or adverse (43%) risk disease by ELN 2022 criteria. 51% (n=82) had co-mutated FLT3 (ITD or TKD). Among pts with FLT3 mutated AML, 30% (37%) also had co-mutated NPM1. 10 (7%) pts had co-mutant NPM1 m without FLT3 m. Median OS in the ND cohort was 19.8 months. Variant allele frequency (VAF) ranges of WT1 m were 1-98 (median 27) and 1-97 (median 13) in the ND and RR cohorts respectively. OS was affected by mutational profile (table 1) with triple mutated NPM1/FLT3/WT1 exhibiting worse OS compared to others. 68% of ND pts received intensive chemotherapy (+/- venetoclax (VEN)) at time of diagnosis with mOS of 26.5 mos vs. 11.1 mos (p = <0.0001) for pts treated with lower intensity therapy (+/- VEN). Improved OS was observed in pts with ELN2022 favorable risk disease (mOS not reached (NR)) and in pts receiving an allogeneic hematopoietic stem cell transplant (SCT). Pts with ND AML and ELN2022 intermediate-risk disease who underwent SCT had significantly longer OS of 47.9 mos vs. 11.8 mos (p<0.0001, figure 1). In the ND cohort, pts had significantly improved OS if they underwent SCT after achievement of CR1 compared to SCT after first relapse, mOS NR vs. 38 months (p=0.00039), respectively. Notably, the median age of pts who received SCT was 50 (22-74) with 16% having secondary (s-AML) or therapy related (t-AML). Of those who did not undergo SCT median age was 63 (23-87) and had with 28% of pts with (s- or t-AML). Within the RR cohort, 44 (30%) pts acquired WT1 mutation post SCT. 56 (38%) were FLT3 m (25 pts with co-mutated NPM1) and 10 (7%) NPM1 m mutated (without FLT3 m). The mOS in the RR cohort (from time of WT1 m acquisition) was shorter in pts with co-mutated FLT3/WT1 without NPM1 (table 1). Pts who underwent SCT after WT1 macquisition had mOS of 25.7 mos (95% CI 23.8-38.7) compared to 18.3 mos (95% CI 13.2-21.2) (p=0.001) in those who did not undergo SCT. 28% of pts received intensive therapy (+/- VEN) as salvage after acquisition of WT1 mwithout difference in OS compared to those receiving low intensity therapy (66% with VEN). mOS (11.1 vs. 7.8 mos, p=0.12) . In pts ND AML and co-mutant NPM1/WT1, WT1 m was frequently (75%) subclonal to NPM1 m with a mOS NR. However, in pts who initially had NPM1 m disease and acquired a WT1 m at relapse, WT1 m was more clonally co-dominant with NPM1 mwith a mOS of 15.9 mos (p=0.11). Amongst both cohorts, there was no difference in survival based on sex. Conclusion WT1 mutations are enriched in intermediate and adverse risk AML, frequently acquired at relapse, and are associated with overall poor OS in the absence of SCT. Our data suggests that pts with WT1m AML benefit from high intensity induction regimens and SCT at CR1 should be considered in all WT1 m pts with ELN2022 intermediate or adverse risk disease. WT1 mutations should also be considered for inclusion into ELN risk stratification given poor overall survival without SCT.

The gut microbiome: Bridging medications and clinical outcomes post stem cell transplantation

Anti-cancer therapies are usually intertwined with prolonged use of drugs, which may lead to different clinical outcomes. Recently in Cell and Cell Host & Microbe, Nguyen etal. and Vallet etal., respectively, deconvolute the drug effects on gut microbiome dynamics underpinning clinical outcomes after allogeneic hematopoietic stem cell transplantation.

Blastocystis sp.—An emerging cause of diarrhea post stem cell transplantation

Protozoans are endemic in the Middle East and diarrhea workup post stem cell transplant should always include stool examination for ova and parasites. We present a case of Blastocystis sp. infection in a multiple myeloma patient who developed diarrhea on day five of post-autologous stem cell transplantation. Diarrhea is a major complication and a potential cause of mortality in this population. Testing for endemic protozoan is recommended.

Cerebrovascular complications of hematopoetic stem cell transplantation in patients with hematologic malignancies

Introduction. Modern transplantation and biological therapy methods are associated with a wide range of adverse events and complications. Incidence and variety of neurological complications mostly depend on myelo- and immunosuppression severity and duration as well as on donor's and recipient's characteristics. The most frequent complications involving the nervous system include neurotoxic reactions, infections, autoimmune and lymphoproliferative diseases, and dysmetabolic conditions as well as cerebrovascular complications that potentially affect transplantation outcomes.
 Objective. To evaluate the impact of post-transplantation cerebrovascular events (CVEs) on transplantation outcomes in patients with hematologic malignancies.
 Materials and methods. We analyzed 899 transplantations performed at the Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology, and Transplantation, Pavlov First Saint Petersburg State Medical University, from 2016 to 2018. We assessed transplantation parameters and donor's and recipient's characteristics by intergroup comparison, pseudo-randomization (propensity score matching), KaplanMeier survival analysis, and log-rank tests.
 Results. Post-transplantatively, CVEs developed in 2.6% (n = 23) of cases: 13 (1.4%) ischemic strokes and 11 (1.2%) hemorrhagic strokes or intracranial hemorrhages were diagnosed. CVEs developed on days 99.5 39.2 post hematopoetic stem cell transplantation (HSCT). There were more patients with non-malignant conditions in the CVE group as compared to the non-CVE group (21.7% vs 7.9%; p = 0.017). Patients with CVE had a significantly lower Karnofsky index (75.6 21.3 vs 85.2 14.9; p = 0.008). Statistically, we also note some non-significant trends: patients with CVE more often underwent allogenic HSCT (82.6% vs 64.0%; p = 0.077) while donors were more often partially (rather than totally) HLA compatible for recipients (39.1% vs 21.1%; p = 0.33). Patients with CVE more often had a history of venous thromboses (13.3% vs 4.2%; p = 0.077). Post-HSCT stroke decreased post-transplantation longevity by approximately 3 times (331.8 81.6 vs 897.9 25.4 post HSCT; p = 0.0001). In the CVE group, survival during first 180 days post HSCT (landmarks post-HSCT Day+60 and Day+180) was significantly lower as compared to that in the CVE-free group. If CVE developed during first 30 days and 100 days post HSCT, vascular catastrophe did not affect post-HSCT survival significantly.
 Conclusion. Whereas ischemic stroke is a long-term HSCT complication (beyond D+100 post transplantation), hemorrhagic stroke is a short-term complication (D0D+100 post HSCT). CVEs affect survival in patients with hematologic malignancies, especially those developed between D+60 and D+180 post HSCT. History of venous abnormalities, low Karnofsky index at HSCT initiation, and the type of allogenic HSCT, especially from half-matched donors, can be considered as negative outcome risk factors in post-HSCT CVE.

Treating childhood acute lymphoblastic leukemia relapse post haploidentical stem cell transplant with car-T cell therapy

Treating childhood acute lymphoblastic leukemia relapse post haploidentical stem cell transplant with car-T cell therapy

PROSPECTIVE SINGLE CENTER ANALYSIS OF OUTCOME STEM CELLS TRANSPLANTS IN PATIENTS WITH CEREBRAL PALSY.

Aim: To evaluate efficacy and safety of autologous bone marrow-derived mononuclear stem cell transplantation intrathecal in children with cerebral palsy. Materials and Methods: 35 children have levels I-V cerebral palsy aged 8-months to 8-years-old were enrolled from September (2021-2022) at Iraqi private hospital. Gross Motor Function was assessed by a pediatrician and neurologist specialist, 5 mcg/kg/day of G-CSF subcutaneous single injection daily for three consecutive days. Bone marrow harvested from posterior iliac crest under light general anesthesia. Bone marrow mononuclear cells (BMMNCs) separation was performed using density gradient centrifugation with Ficoll, the cell viability checked by propidium iodide dye in a TALI machine (Invitrogen) in average 98%. The viable BMMNCs injected intrathecal in L4-L5 over a period of 5-10 min. Results: Males accounted for 57.14% (20/35) while female 42.86% (15/35), and main neurological symptoms included spastic disorder spastic disorder (quadriplegia 24 (68.6), tetraplegia 2 (5.7), diplegia 5 (14.28), hemiplegia4 (11.42)). Gross Motor Function Classification System and Gross Motor Function Measure-66 (GMFM-66) showed II 10 (28.58), III 11(31.42) and IV 14 (40). On mean follow-up of 3 months post-stem cell transplant improvement was observed in 80% cases. The improvement showed in gross motor function (6/8) p=0.01, and speech (2/4) p=0.04, neck holding (5/5) p=0.0003, sitting balance (4/4) p=0.04, postural tone (5/5) p=0.0003, as well as significant reduction in seizure frequency (2/3) p=0.04 and improvement in cognition (6/7) p=0.01 were observed. Conclusion: Stem cell therapy for cerebral palsy shows a significant positive effect on the gross motor function, without long adverse effects.

Thoracic air leak syndrome as the sole manifestation of chronic lung graft-versus-host disease: a case report

BackgroundThoracic air leak syndrome (TALS) is a rare complication associated with chronic lung graft-versus-host disease (GVHD) and bronchiolitis obliterans syndrome (BOS). In the present case, TALS was the sole pulmonary manifestation of GVHD.Case presentationA 30-year-old woman presented with dyspnea on exertion and swelling of the neck and face after allogeneic stem cell transplantation for acute myeloid leukemia. She was found to have subcutaneous emphysema, and chest imaging suggested pneumomediastinum, with normal lung parenchyma. Her clinical and radiological findings indicated TALS. There were no other features suggestive of lung GVHD. Her condition improved with conservative management and increased immunosuppression. However, she subsequently had two relapses, developed severe infection and pneumothorax, and died.ConclusionsThe present case report illustrates a unique presentation of TALS, a rare complication of GVHD, in a post-stem cell transplant patient. It highlights the challenges in the diagnosis and management of this condition.

Siremadlin Monotherapy and in Combination with Donor Lymphocyte Infusion for Patients with Acute Myeloid Leukemia Post Allogeneic Stem Cell Transplantation Who Are in Complete Remission but at High Risk for Relapse

Background: Relapse post allogeneic stem cell transplantation (SCT) remains the main cause of treatment failure (~40%) for patients (pts) with acute myeloid leukemia (AML). Many pts who ultimately relapse post SCT do so within the first year post transplant, and earlier relapse is associated with poorer survival. Therapeutics that prevent early relapse for these pts are urgently needed. Early cellular or pharmacologic intervention or maintenance strategies that enhance the graft-versus-leukemia (GvL) effect after SCT are of renewed interest as they have the potential to reduce relapse risk post SCT. Siremadlin (HDM201) is a novel investigational MDM2 inhibitor with single-agent, anti-AML activity. MDM2 inhibitors, including siremadlin, possess potent immunomodulatory effects in murine solid tumor and AML models. MDM2 inhibition has been shown to synergize with the allogeneic immune response, increase the vulnerability of AML cells to allogeneic donor T cells, and promote the cytotoxicity and longevity of allogeneic donor T cells in murine models. As such, the post-SCT setting is ideal for investigating the immunomodulatory effects of MDM2 inhibition on enhancing the GvL effect (Ho et al. Blood. 2022). Here we describe the design of a Phase Ib/II, open-label study of siremadlin as monotherapy and in combination with donor lymphocyte infusion (DLI) in pts with AML post SCT who are in complete remission (CR) but at high risk for relapse based on the presence of pre-SCT risk factors (NCT05447663). Study Design: The trial is not yet recruiting but aims to enroll ~38 adult pts with AML who underwent first SCT and are currently between Day 60-120 post SCT. Prior to a patient's SCT, they must have a risk factor that puts them at high risk for relapse, including AML in first CR with adverse risk genetics per 2017 European LeukemiaNet risk stratification, therapy-related AML, or secondary AML; or AML in second or greater CR. The SCT must be from an 8/8 human leukocyte antigen (HLA) matched related or unrelated donor at HLA-A, -B, -C, -DRB1 loci using unmanipulated/T-cell replete bone marrow or peripheral blood stem cells as a stem cell source. Post SCT, pts must have achieved CR or CR with incomplete hematologic recovery (CRi) with no evidence of hematologic relapse. Exclusion criteria include prior exposure to an MDM inhibitor, active graft-vs-host disease (GvHD), past history of grade ≥III acute GvHD (aGvHD) or moderate/severe chronic GvHD (cGVHD), recipient of SCT from a haploidentical family donor or cord blood transplant, and prior systemic AML-directed treatments given at any time after SCT (including DLI). This study contains 2 parts, Part 1 is a dose confirmation of siremadlin monotherapy and will enroll ~12 pts. Siremadlin will be tested at a maximum of 3 dose levels with a starting dose of 30 mg/d on Days 1-5 of a 28-day cycle, dose level +1 at 40 mg/d and dose level -1 at 20 mg/d. The safety and tolerability of these dose levels will be assessed to determine the siremadlin recommended dose (RD) for Part 2. Pts in Part 1 of the study will receive siremadlin monotherapy for the entire duration of the treatment and will not receive DLI. Subsequently, ~26 pts will be enrolled in Part 2 and proceed through a priming phase with siremadlin monotherapy at the RD, followed by a combination phase of siremadlin + DLI, and subsequently a maintenance phase with siremadlin monotherapy (Figure). Primary safety endpoints of the study are incidence of dose-limiting toxicities (DLTs) in Part 1 and time to DLT in Part 2. The primary efficacy endpoint is the proportion of pts in Part 2 who are alive and maintained CR/CRi without hematologic relapse ≥6 months after the start of study treatment. Secondary endpoints include number of pts in Part 1 who are alive and maintained CR/CRi without hematologic relapse ≥6 months after the start of study treatment at the RD for Part 2, time to first documented hematologic relapse or death, incidence of relapse at 1 year and 2 years post study treatment, safety, GvHD-free/relapse-free survival, incidence of and time to treatment-emergent grade ≥III aGvHD or moderate/severe cGvHD, and pharmacokinetics. Conclusions: This Phase Ib/II study investigates siremadlin monotherapy and siremadlin in combination with DLI in pts with AML in remission but at high risk of relapse post SCT. The study will evaluate the unique immunomodulatory potential of siremadlin to reduce risk of relapse in this population with high unmet need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Frontline Combination of Hyper-CVAD with Ponatinib for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia-6-Year Follow-up Results

Background: The combination of cytotoxic chemotherapy with a BCR::ABL1 tyrosine kinase inhibitor (TKI) has historically been standard of care for patients (pts) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is 3rd generation TKI with more potent BCR::ABL1 inhibition than earlier-generation TKIs. Ponatinib also suppresses T315I clones, which are responsible for most relapses with other TKIs. Here we present the 6-year follow-up results of hyper-CVAD plus ponatinib for patients with newly diagnosed Ph+ ALL. Methods: This was a phase 2, single-arm study to evaluate the efficacy and safety of hyper-CVAD with ponatinib in adults with newly diagnosed Ph+ ALL. Pts age 18 years or older with previously untreated Ph+ ALL were eligible; pts who had received 1 to 2 courses of prior chemotherapy, with or without a TKI, were also eligible. Pts were required to have an ECOG performance status of 2 or less, bilirubin <3mg/dl, creatinine <3mg/dl, and normal cardiac function. Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for 8 cycles. Initially, ponatinib was given at a dose of 45 mg daily. Due to 2 deaths due to cardiovascular events related to ponatinib, beginning with pt #37, the protocol was amended. After the amendment, ponatinib was administered at a dose of 45 mg for 14 days in cycle 1, then 30mg daily once patients achieved CR and 15mg daily once a complete molecular response (CMR) was achieved. Maintenance therapy was given for 2 years, vincristine, prednisone and ponatinib. Pts received 12 doses of intrathecal chemotherapy with alternating doses of cytarabine and methotrexate. Results: 86 pts were treated. Pts characteristics are summarized in Table 1. The median age was 46 years (range 21-80). Sixty-six pts (77%) had received no prior ALL-directed therapy, and 20 pts (23%) had received 1-2 courses of therapy prior to enrollment. Among these 20 pts, 18 were in CR and 2 had persistent disease at the time of enrollment. Sixty three pts (73%) had a p190 transcript, and 21 (24%) had a p210 transcript. Among 68 pts with active disease at enrollment, all pts achieved CR. Among 54 pts evaluable for cytogenetic response, all pts achieved complete cytogenetic response, including 50 pts (93%) after 1 cycle. Among 85 pts evaluable for molecular response, 83 pts (98%) achieved at least a major molecular response and 73 pts (86%) achieved a CMR. No pts died in the first 4 weeks of therapy. After a median follow up of 75 months (range, 16-123+ months), the 5-year overall survival (OS) and relapse-free survival rates were 75% and 68%, respectively (Figure 1). Twenty pts (23%) underwent stem cell transplantation (SCT) in first remission (5 of whom relapsed post SCT and 1 of whom died from post-SCT complications), 10 pts (12%) died in CR, 13 pts (19%) relapsed without SCT, and 43 pts (50%) are in ongoing remission without SCT. Of the relapsed pts, 5 were on ponatinib at the time of relapse, 2 of whom acquired an E255K kinase domain mutation at relapse; and 5 were on imatinib or dasatinib at the time of relapse, 3 of whom acquired a T315I kinase domain mutation. Among the 10 deaths in CR, 2 were treatment-related (both due to myocardial infarction before the amendment to implement lower doses of ponatinib). In a 8-month landmark analysis, the 5-year OS for pts without ASCT and with ASCT were 87% and 70%, respectively (p =0.09). Among the pts who are in ongoing remission without ASCT, 3 received subsequent therapy for MRD-positive disease. The most common grade ≥3 AE was infections and/or febrile neutropenia, seen in 82 pts (95%). Other grade ≥3 AEs including elevated transaminases in 25 pts (29%), increased amylase and/or lipase in 15 (17%), hyperbilirubinemia in 13 pts (15%), and clinical pancreatitis in 13 pts (15%). Five pts (6%) had a grade ≥3 venous thrombotic event, and 5 pts (6%) had a grade ≥3 arterial cardiovascular event. Two patients died from ponatinib-related cardiovascular complications, both from MI during cycle 2. Conclusion: The combination of hyper-CVAD and ponatinib results deep and durable remissions in pts with newly diagnosed Ph+ ALL. The overall CMR rate was 86% and the 5-year OS was 75%, which compares favorably with regimens using first- or second-generation TKIs in this population. The combination was safe; the use of lower doses of ponatinib maintained efficacy and mitigated the risk of ponatinib-related toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal