Extramedullary Research Articles

Myeloid sarcoma, spectrum of clinical characteristics, prognostic impact, and treatment outcome

BackgroundAcute leukemia may present with extramedullary (EM) tissues. Myeloid sarcoma (MS) and leukemia cutis (LC) are considered extramedullary diseases. This study aims to evaluate the incidence, clinical characteristics, and prognostic factors affecting the outcome of pediatric patients with myeloid sarcoma at the pediatric oncology center from July 2007 to December 2017. Radiological imaging was used to stage the tumor, biopsy was done for pathological diagnosis, and bone marrow aspirate for morphology, flow cytometry, cytogenetics, and molecular analysis. Patients received chemotherapy protocols based on those used by the Children's Cancer Group for acute myeloid leukemia (AML).ResultThe study included 91 (13.2%) of 687 pediatric patients with acute myeloid leukemia, with a male-to-female ratio of 1.9 to 1. Prognostic factors that improved the patient’s 5-year overall survival (OS) were age > 5 years old, molecular and cytogenetic detection of t (8; 21), inv 16, presence of a single and small size lesion < 5 cm, negative CNS lesion, and achieved radiological response in isolated disease or radiological and marrow complete remission in disseminated disease post induction 1 with significant P value. Relapse, particularly early relapse, worsens the OS and EFS by 10% and 7.7%, respectively.ConclusionPatients over five with low-risk disease based on cytogenetics, a small, single, negative CNS lesion, and a complete response post induction 1 had better outcomes, with no significant difference between those with isolated extramedullary disease and those with marrow dissemination. Early relapse harms the outcome. The study group’s 5-year OS and EFS rates are 51.4% and 49.4%, respectively.

Extra Medullary Fixation in Unstable Proximal Femoral Fractures by PF-LCP.

Perception that extra-medullary fixation of these fractures are fraught with difficulties and deficiencies is becoming inappropriate. This device provides angular stable fixation retaining fracture biology with minimum interference to osseous and soft-tissue vascularity and it does not require reaming which destroys 80% of endosteal vasculature for 6-12weeks. PFLCP averts iatrogenic fracture in lateral trochanteric wall (LTW) which is frequent with DHS, protects LTW from secondary fracture in post-operative period. Aim is to assess outcome of unstable proximal femur fracture fixation by PFLCP. Study included 64 from 2016 to 2020, divided in two groups. (A) Unstable intertrochanteric fracture and (B) subtrochanteric fracture (Seinsheimer types II-V). All fractures fixed by MIPO with PFLCP. Loss of reduction, infection, cut-out, cut-through, backing of screws, bending or breaking of plate and screw, malunion, non-union and revision were evaluated. Fracture healing and functional recovery assessed by Reborne Score and Parker Mobility Score (PMS) respectively. Out of 64, 24 achieved pre-injury PMS, 32 declined by 1 point, 6 declined by 2 points and 1 by 3 points, one required revision. Using various parameters 37.5% patients had excellent results and 50% had good results, 9.38% had average and 3.12% had poor result. None reported non-union or breakage of plate. PFLCP provides angular stable fixation, torsional stability with high biomechanical strength to resist deforming stresses. MIPO avoids soft-tissue stripping reducing blood-loss, retains periosteal blood supply to inter-fragmentary bone fragments, enhancing fracture healing, reducing complications, such as delayed healing, nonunion, infection and implant failure.

Clinical features associated with poor response and early relapse following BCMA-directed therapies in multiple myeloma

Three classes of BCMA-directed therapy (BDT) exist: antibody drug-conjugates (ADCs), CAR-T, and T-cell engagers (TCEs), each with distinct strengths and weaknesses. To aid clinicians in selecting between BDTs, we reviewed myeloma patients treated at Mayo Clinic with commercial or investigational BDT between 2018-2023. We identified 339 individuals (1-exposure = 297, 2-exposures = 38, 3-exposures = 4) who received 385 BDTs (ADC = 59, TCE = 134, CAR-T = 192), with median follow-up of 21-months. ADC recipients were older, with more lines of therapy (LOT), and penta-refractory disease. Compared to ADCs, CAR-T (aHR = 0.29, 95%CI = 0.20–0.43) and TCEs (aHR = 0.62, 95%CI = 0.43–0.91) had better progression-free survival (PFS) on analysis adjusted for age, the presence of extramedullary (EMD), penta-refractory disease, multi-hit high-risk cytogenetics, prior BDT, and the number of LOT in the preceding 1-year. Likewise, compared to ADCs, CAR-T (aHR = 0.28, 95%CI = 0.18–0.44) and TCEs (aHR = 0.60, 95%CI = 0.39–0.93) had superior overall survival. Prior BDT exposure negatively impacted all classes but was most striking in CAR-T, ORR 86% vs. 50% and median PFS 13-months vs. 3-months. Of relapses, 54% were extramedullary in nature, and a quarter of these cases had no history of EMD. CAR-T demonstrates superior efficacy and where feasible, should be the initial BDT. However, for patients with prior BDT or rapidly progressive disease, an alternative approach may be preferable.

Atypical Presentation of Acute Suppurative Otitis Media with Facial Palsy: Extra Medullary Manifestation of AML in Temporal Bone.

Acute Myeloid Leukemia (AML) is the most common leukemia observed in the adult population, accounting for 80% of all leukemia cases. Extramedullary involvement in AML, where leukemic cells are found in organs or tissues outside the blood or bone marrow, is a rare occurrence [1]. The most frequent sites of extramedullary disease include the skin, central nervous system (CNS), and lymph nodes [2, 3]. In this case report, we present an instance of extramedullary AML in the temporal bone, which initially presented with symptoms such as earache, discharge, and facial asymmetry, mimicking acute suppurative otitis media with facial palsy. The patient underwent mastoid exploration and facial nerve decompression. A post-operative bone marrow biopsy confirmed the diagnosis of AML, leading to the initiation of chemotherapy. The patient is currently under follow-up care.

Comparable Outcomes of Relapsed Acute Lymphoblastic Leukemia in Adolescents and Young Adults (AYA) Patients Treated with Pediatric-Inspired Chemotherapy (R3 protocol) Versus Adult-Based Salvage (FA) Protocol

Background Although the survival rate of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) has improved by using pediatric-based treatment protocols, those who experience a relapse still have poor outcomes when treated with adult chemotherapy salvage-regimens, which have traditionally included high doses of Ara-C. The long-term survival rate for patients treated with these salvage-regimens is less than 10%. Salvage treatment with blinatumomab for adults with relapsed B-cell ALL results in a complete remission (CR) rate of 34%, a median survival of 7.7 months, and an overall survival (OS) of less than 30% at 18 months. In contrast, the ALLR3 protocol for relapsed ALL in patients up to the age of 18 years achieved a CR rate of 97% and an overall survival rate of 72%. Therefore, this study aims to compare the outcomes of AYA patients treated with pediatric-inspired regimen (R3 regimen) to those treated with adult-based regimen (FA (Fludarabine/Cytarabine) protocol). Methods The R3 protocol treated 17 AYA patients with relapsed Philadelphia-negative ALL, aged between 14 to 40 years old, who had received first-line therapy. Patients who achieved CR underwent allogenic transplant. The protocol included vincristine, mitoxantrone, asparaginase, dexamethasone, and intrathecal methotrexate. In comparison, 60 patients were treated with FA protocol, with patients achieved CR proceeded to allogeneic stem cell transplantation. Relapses were classified as very early (&amp;lt; 18 months from diagnosis), early (&amp;gt;18 months from diagnosis and &amp;lt;6 months from the end of therapy), and late (&amp;gt;6 months from the end of therapy). Patients' characteristics, response rate (RR) and overall survival (OS) were analyzed. Results The two arms had comparable characteristics. The median age in the R3 arm was 16 years (range: 14-40 years) compared to 22 years (range: 18-32 years) in the FA protocol arm. In the R3 arm, 88.2% of patients had B-cell ALL, while in the FA protocol arm, 92.2% had B-cell ALL. CNS involvement was seen in 28.8% and 17.6% of cases in the R3 and FA protocol arms, respectively. Relapses were classified as very early, early, or late in 2 (12%), 5 (29%), and 7 (41%) of cases in the R3 arm and were mostly late (25.2%) in the FA protocol arm. Relapses in the R3 arm were isolated bone marrow (BM), isolated extramedullary (EMD), or combined BM and EMD in 14 (82%), 1 (6%), and 2 (12%) cases, respectively, while EMD was around three times higher (16.9%) in the FA arm. The overall CR rate was 60% at the end of R3 induction, with negative MRD (&amp;lt;10 −4 cells) in 47.1% of patients. The overall CR rate was higher in the FA arm (76.3%), but the difference with the R3 arm was not statistically significant (p-value 0.1). The disease was refractory to subsequent salvage therapy in 42% of cases in both arms. About half of the patients who responded to R3 proceeded to allogeneic stem cell transplant (52.3%), while 78% of the patients post-FA underwent transplantation. Eight patients died (47%) in R3 arm, but only one patient died due to treatment-related sepsis, while the other seven patients died due to disease-related causes. At a median follow-up of 4 years, OS was 53% in the R3 arm compared to 30.8% in the FA arm, but the difference was not significant (p-value=0.8). The post-FA mortality was mainly due to infections (15.3% in FA vs. 5.9% in R3). Conclusion Pediatric-inspired protocols that have shown significant benefits in the front-line setting for ALL in the AYA population did not demonstrate a significant difference when compared to traditional adult-based salvage chemotherapy regimens in relapsed disease.

Durable MRD and Imaging-Negative Remission ≥ 5 Years Post-Therapy Predicts Long-Term Progression-Free Survival in Multiple Myeloma Patients - a Single-Center Observational Study

Introduction With the advent of modern multiple myeloma (MM) therapies, a significant proportion of patients can achieve durable clinical remission. Minimal residual disease (MRD) reflects depth of response and is a powerful predictor of progression-free survival (PFS) (Munshi et al, JAMA Oncology 2017). Although sustained MRD negativity (defined by IMWG as MRD-negative on two occasions, minimum one-year apart) is associated with improved PFS, there is continued long-term relapse in these patients. A recent study reported a 10-year PFS of 88% in MM patients who are MRD-negative &amp;gt; 3 years after total therapy (Mohan et al, Blood Advances 2022). In the current era of regular MRD testing in MM care, we aimed to estimate the 10-year PFS of unselected MM patients who are MRD and imaging-negative ≥ 5 years after latest therapy, using our single-center data. Methods MRD testing was introduced for MM patients in remission at the Icahn School of Medicine at Mount Sinai (ISMMS) in 2017. Therefore, we systematically reviewed all patients with MRD results in the ISSMS MM registry between July 2017 and December 2022. Next-generation multi-parametric flow cytometry (NGF) was used to detect MRD from 2017 to 2021, with the addition of next-generation sequencing (NGS) from 2021 onwards. MRD-negativity was defined as &amp;lt;1 in 10 5 by NGF or &amp;lt;1 in 10 6 by NGS, and one representative MRD result per year was taken for analysis. Whole-body positron emission tomography (PETCT) and MRI were used to evaluate bone or extra-medullary (EM) disease. Detailed retrospective chart review of patients with sequential MRD-negative results was conducted to identify those with durable clinical, MRD, and imaging negative remission. PFS was evaluated using Kaplan-Meier curves and survival estimates. Results Between 2017 and 2022, 1703 MM patients underwent MRD testing at our center. Of these patients, we have so far identified 92 patients who were in CR, MRD and imaging-negative ≥ 5 years after the start of latest therapy. The estimated 10-year PFS in our cohort was 91.4% (95% CI [0.833 ,1]; Figure 1). With a median follow-up time of 5.9 years (4.6 to 12.6 years), the majority of our cohort (75%) were off-therapy at last follow-up with a median time-off-therapy of 2.5 years. In terms of baseline patient and disease characteristics (Table 1), 57.6% patients were white and 60.9% were male. Most patients were ISS stage I (51.1%) with standard-risk cytogenetics (78.2%) at diagnosis. A much smaller proportion of our cohort had any adverse cytogenetics, including gain1q (13%) and del17p or TP53 mutation (7.6%). The majority of patients were in their first remission after frontline therapy (52.2%), with 33.7% having received autologous stem cell transplant (ASCT) first-line. A smaller proportion of the cohort had received salvage treatment; 31.5% had received two lines, 16.3% had received ≥ 3 lines. Four patients relapsed in this cohort (4.3%) and one patient died of a non-MM related cause. Of the patients who progressed, 2 relapsed with isolated biochemical disease and 2 with predominantly EM disease. Both biochemical relapses were preceded by conversion to MRD positivity by NGF 6 months to 1 year prior, whereas those relapsing with EM disease remained MRD negative. Three patients had been off-treatment between 1 to 4 years prior to clinical relapse and the fourth patient progressed whilst on maintenance treatment. Conclusion We report single-institution MRD data on unselected MM patients who have durable MRD and imaging-negative remission for at least 5 years from their latest line of therapy. The estimated 10-year risk of disease-progression in our cohort is around 8.6%, with the majority of patients being off-therapy. The low rate of disease-progression at 10 years demonstrates that a proportion of MM patients do not suffer multiple relapses and may therefore be potential candidates for discontinuation of maintenance. From our data, these patients are more often ISS stage I, have standard risk cytogenetics and achieve deep responses to frontline therapy. A smaller proportion of patients are able to achieve this landmark even after salvage therapies. This may be increasingly possible in the era of monoclonal antibodies and T cell redirection therapies. Analysis of larger real-world MM cohorts is needed to elucidate whether sustained MRD-negative remission at 5 years can truly predict long-term disease-free survival and possible cure.

Comparison of Intramedullary and Extramedullary Fixation Results in Subtrochanteric Femur Fractures.

The subtrochanteric femur is a load-bearing region where deforming forces are effective. These fractures are difficult to treat for orthopedic surgeons. In this article, we aimed to compare intramedullary (IM) and extramedullary (EM) fixation methods for these fractures that do not have gold standard treatment. Eighty-five patients were retrospectively evaluated. Patients with IM implants (IM femoral nail, proximal femoral nail) were grouped as Group 1, and patients with EM implants were grouped as Group 2 (95° condylar plate, locked anatomical proximal femoral plate). Patients' age, gender, fractured hip side, etiology, anesthesia type, preoperative waiting time, follow-up period, fracture type, Harris hip score (HHS), and mechanical complications were examined. The mean age of the patients was 44.13 years. There was no difference between the groups in terms of age and gender. The mean follow-up period of the patients was 13.28 months. Falling from a height was the most common cause of subtrochanteric fracture. IM fixation was applied to 62 patients, and EM fixation was applied to 23 patients. No significant difference was found between Groups 1 and 2 in non-union, delayed union, implant failure, shortness rates, and HHS. Both IM and EM fixation methods have advantages and disadvantages in treating subtrochanteric fractures. These methods yield similar results in both groups in our study. The issue of fixation methods remains controversial in the literature, and further studies are needed on this subject.

4SCAR2.0 therapy for the management of post-transplantation relapse of B-cell acute lymphoblastic leukemia

IntroductionAllogeneic hematopoietic stem cell transplantation (allo-HCT) is a standard treatment for relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). However, about 30-40% of patients still relapse after HCT. Chimeric antigen receptor-modified T-cell (CAR-T) therapy has been proven effective in the treatment of relapsed or refractory B-ALL.Patients and methodsWe report a cohort of 30 B-ALL patients, who relapsed after HCT and were enrolled in the 4SCAR2.0 study, receiving CD19 CAR-Ts alone (20 patients), or two types of CAR-Ts targeting CD19, CD22, CD38 or CD123 antigens (10 patients), depending on the tumor antigen expression profile. These patients had extramedullary (EM) relapse or bone marrow (BM) relapse, or both. Based on the GVHD history, donor chimerism, and the available T-cell source, 25 patients received allogeneic donor CAR-Ts, and 5 patients received autologous CAR-T treatment. ResultsAll 20 patients receiving a single CD19 CAR-T infusion achieved a minimal residual disease (MRD) remission within 60 days. The remaining 10 patients, due to low CD19 antigen expression profile, received 2 CAR-T products given on the same day, and 9 of 10 achieved complete remission (CR) and one had disease progression within 60 days. After CAR-T infusion, no cytokine release syndrome (CRS) was observed in 14 patients, and 16 patients experienced grade 1 CRS, and there was no neurotoxicity. Seventeen of the 30 patients who achieved remission (57%) remained in continuous remission following CAR-T treatment with a median follow-up period of 2 years and a median duration of remission of 12 months (range: 2.8 months - 67 months). Twelve out of 29 patients (41%) who achieved remission, subsequently relapsed at a median of 6.3 months (range: 2.8 months - 22.3 months) after CAR-T treatment. In summary, 29 patients (97%) achieved MRD negative remission within 60 days of therapy with a single or double CAR-T infusion, and seven patients remained in durable remission (7/30, 23%) after more than 2 years of follow-up. DiscussionThe tumor antigen profile-guided precision 4SCAR2.0 regimen for the treatment of r/r B-ALL after allo-HCT was highly effective with low toxicity. This approach warrants extended follow-up and further studies. Clinical trial registrationClinicalTrials.gov, identifier NCT03125577.

“Dose-Dense” Mini-Hyper-CVD, Inotuzumab Ozogamicin and Blinatumomab Achieves High Rates of Rapid MRD-Negativity in Patients with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia: A Retrospective Analysis

Background: Mini-hyper-CVD plus inotuzumab ozogamicin (InO) followed by sequential blinatumomab (Blina) is effective in both older adults with newly diagnosed B-cell ALL and in relapsed/refractory disease. We hypothesized that concomitant administration of these agents in a “dose-dense” (DD) fashion would also be safe and effective in B-cell acute lymphoblastic leukemia (ALL), leading to rapid measurable residual disease (MRD) negativity. Methods: This is a retrospective analysis of patients (pts) with B-cell ALL who received DD mini-hyper-CVD + InO + Blina outside of a clinical trial. All pts received mini-hyper-CVD alternating with mini-methotrexate and cytarabine in combination with InO. To be evaluable for this analysis, Blina must have started prior to day 21 of the first cycle of therapy. Pts were included if they received this regimen for 1.) frontline induction, 2.) treatment of MRD-positive remission, or 3.) salvage therapy for relapsed/refractory (R/R) disease. Results: Between 7/2020 and 1/2023, 21 eligible pts were treated (Table 1 ). The median age was 48 years (range, 6-74 years); 3 pts (all in the R/R cohort) were &amp;lt;18 years old. 9 pts (43%) were treated as frontline therapy, 4 (19%) for treatment of MRD (3 for flow-positive MRD and 1 for persistent FISH for t[4;11]), and 8 (38%) for R/R disease. In the MRD cohort, 3 pts were in first CR and 1 was in second CR; 1 pt received prior InO and 1 had prior allogeneic stem cell transplant (alloSCT). In the R/R cohort, pts were heavily pretreated, with a median number of prior therapies of 3 (range, 1-7); 2 pts received prior InO, 3 pts received prior Blina, 3 pts had undergone prior allo SCT, and 3 pts had received prior chimeric antigen receptor T-cell (CAR-T cell) therapy. Three pts (all in the R/R cohort) had extramedullary (EM) disease, 2 outside of the CNS without marrow disease and 1 with CNS disease and bone marrow MRD by flow. Pts received a median of 2 cycles (range, 1-5) of a dose-dense regimen. All pts received 0.9 mg/m 2 InO in cycle 1, except for 1 pt in the R/R cohort who received 0.6 mg/m 2 due to myelosuppression with prior InO. Themedian cumulative dose of InO was 1.2 mg/m 2 (range, 0.6-2.7 mg/m 2). Blina was started on a median of day 4 (range, day 4-17) of the first cycle of chemotherapy. Blina was started by day 7 in 16 pts (76%). In the frontline cohort, all pts (100%) achieved CR/CRi (CR in 8 pt and CRi in 1 pt), all after cycle 1 ( Table 2). All pts in the frontline cohort achieved flow MRD negativity. 7 pts were evaluable for bone marrow next generation sequencing (NGS) MRD (sensitivity 10 -6). Of these, 4/6 (67%) achieved NGS MRD negativity after cycle 1, and all 7 evaluable pts (100%) achieved NGS MRD negativity. In the MRD cohort, all 3 flow-positive pts became flow MRD negative after cycle 1; the pt with positive FISH for t(4;11) became FISH-negative after cycle 2. 3 of the 4 pts in the MRD cohort (75%) became NGS MRD negative. Overall, 5 of the 8 pts (63%) in the R/R cohort achieved CR/CRi. Among 5 evaluable pts in the R/R cohort with marrow disease (including the pt with CNS disease and MRD-positive marrow), all achieved flow MRD negativity after cycle 1. Overall, 7 pts (33%) underwent consolidative alloSCT (2 in the MRD cohort and 5 in the R/R cohort), and 1 pt in the MRD cohort underwent consolidative CAR-T cell therapy. The treatment regimen was well tolerated. No patients developed sinusoidal obstruction syndrome/veno-occlusive disease. One pt had grade 1 CRS, and 2 pts had grade 1 tremor. With a median follow-up of 13.4 months (range, 0.5-20.6 months), 6 pts (29%) have died (1 in the frontline cohort, 1 in the MRD cohort and 4 in the R/R cohort). 3 deaths were due to complications of alloSCT, 2 were due to sepsis (1 in the setting of refractory leukemia and 1 during MRD-negative CR), and 1 from unknown cause. Among 18 responding pts, only 1 pt relapsed; the pt with MRD-positive t(4;11) by FISH relapsed 4.5 months after alloSCT. The median OS for the R/R cohort was 5.8 months and was not reached for the frontline or MRD cohorts. The 1-year OS rate for the frontline + MRD cohort was 83%. Conclusion: Dose-dense mini-hyper-CVD in combination with InO and Blina achieves rapid MRD-negative remissions in patients with B-cell ALL. All responding patients achieved flow MRD negativity after 1 cycle of therapy, with the majority also achieving NGS MRD negativity. This regimen is now being prospectively evaluated in an ongoing clinical trial in pts with R/R B-cell ALL and in older adults with newly diagnosed B-cell ALL.

Chemotherapy-Sparing Induction Followed By Consolidation and Maintenance with Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy for Newly-Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Primary Endpoint Results from the Blissphall Study

Background: Oral ABL-targeted kinase inhibitors (TKIs) have transformed treatment of BCR::ABL+ (Philadelphia chromosome-positive, Ph+) acute lymphoblastic leukemia (ALL). Induction (IND) w/ corticosteroids (CS) and dasatinib (DAS) alone results in morphologic complete response (mCR) rates approaching 100% but low rates of measurable residual disease (MRD) negativity; addition of intensive chemotherapy to TKIs adds risks of myelosuppression. DAS + the CD3/CD19 bispecific T-cell engager blinatumomab (BLIN) is effective consolidation (CONSOL) for Ph+ ALL, though ABL kinase mutations conferring resistance can arise early in therapy (Foà, NEJM, 2020). We designed a phase II study of BLIN as part of a chemotherapy sparing strategy in pts w/ Ph+ ALL (BLISSPHALL), introducing BLIN as early as 6 weeks into treatment for pts in mCR, w/ aim of expediting MRD clearance and suppressing resistant clones early in disease course, and including a maintenance (MAINT) phase of BLIN + TKI for pts in molecular response. Methods: We conducted a multicenter trial of TKI + CS IND and TKI + BLIN CONSOL + MAINT in adults (≥18 yrs) w/ newly-diagnosed (ND) Ph+ ALL (NCT04329325). Study schema is depicted in Figure 1. Pts received CS pre-phase w/ prednisone (PRED) or dexamethasone (DEX) followed by modified GIMEMA LAL1205 IND (DEX + DAS 140 mg/d w/ DAS dose adjustments or TKI change per protocol) w/ intrathecal methotrexate (IT MTX) d22, 43 and bone marrow (BM) MRD assessments including FACS and BCR::ABL1 PCR. Pts in mCR on d43 could proceed to CONSOL w/ 3 cycles (C) of TKI + BLIN 28 mcg/d IVCI, d1-28, w/ 14d off BLIN between cycles and BM MRD assessment/IT MTX after each cycle. TKI was given continuously including between BLIN cycles. Pts in protocol-defined complete molecular response (CMR; MRD negative by FACS and no detectable BCR::ABL1 transcripts) after CONSOL could proceed to MAINT (C4-7 BLIN + TKI, 28d off between cycles). The primary objective is to determine the proportion of evaluable pts achieving CMR by the end of CONSOL (≤ 3C BLIN + TKI). Secondary objectives include safety/toxicity of BLIN + DAS, duration of CMR, incidence of relapse, event-free/overall survival. Toxicities were defined by CTCAE v5.0. Results: 17 pts enrolled (12 women, 5 men) w/ median age 50 yrs (range 22-87); BCR::ABL1 transcript type p190 (n=15) or p210 (n=2). Median follow-up 11.7 months (range 3-24). All began DAS 140 mg/d as initial TKI; 4 changed TKI for DAS intolerance per protocol (bosutinib, n=2; ponatinib [PON], n=2) and remained on study; TKI was changed to PON in 1 other pt to optimize BCR::ABL1 transcript suppression pre-allogeneic transplant (alloHCT) and that pt was withdrawn from study. Two had interruption or delay of BLIN due to toxicity (grade [G] 3 transaminase elevation, n=1; G2 cytokine release syndrome, n=1); BLIN was resumed in both. Figure 2 lists nonhematologic adverse effects (AEs) seen in ≥2 pts at least possibly related to TKI or BLIN while on study. One pt developed G3 pancreatitis after DAS was changed to PON; TKI was changed back to DAS. There were no G4-5 AEs. All pts (100%) achieved mCR during IND (median d22). Ten achieved CMR to date (5 during IND, 5 during CONSOL) and 6 did not achieve CMR; determination pending in 1 pt. By FACS, 16/17 achieved BM MRD negativity; 13/14 evaluable pts had no evidence of malignant clonal IgH rearrangement (IgHR) by next generation sequencing (NGS). Notably, 3 pts w/ persistent low-level BCR::ABL1 transcripts had no evidence of malignant clonal IgHR by NGS but were withdrawn post-CONSOL as protocol required BCR::ABL1 PCR negativity to proceed to MAINT. Two pts relapsed, both after achieving CMR (one declined CONSOL and self-discontinued TKI; one had extramedullary (EM) relapse w/ ABL T315I mutation). Four pts underwent alloHCT in CR1 (rising MRD levels on study leading to change in therapy, n=1; persistent BCR::ABL1 PCR positivity, n=2; IKZF1 plus phenotype, n=1); one underwent alloHCT in CR2 following EM relapse. Conclusions: DAS + CS IND w/ addition of BLIN to TKI in mCR leads to high rates of deep molecular response w/ low risk of early relapse and low rates of severe regimen-related toxicity in pts w/ ND Ph+ ALL. Use of PON (vs DAS) as initial TKI w/ BLIN may further suppress resistant clones. Further f/u is needed to confirm durability of CMR w/ BLIN + TKI CONSOL ± MAINT in absence of alloHCT and whether pts w/ persistent BCR::ABL1 PCR positivity and no malignant clonal IgHR by NGS exhibit similar outcomes to those in CMR.

Expression profiling of extramedullary acute myeloid leukemia suggests involvement of epithelial-mesenchymal transition pathways.

Extramedullary (EM) colonization is a rare complication of acute myeloid leukemia (AML), occurring in about 10% of patients, but the processes underlying tissue invasion are not entirely characterized. Through the application of RNAseq technology, we examined the transcriptome profile of 13 AMLs, 9 of whom presented an EM localization. Our analysis revealed significant deregulation within the extracellular matrix (ECM)-receptor interaction and focal-adhesion pathways, specifically in the EM sites. The transcription factor TWIST1, which is known to impact on cancer invasion by dysregulating epithelial-mesenchymal-transition (EMT) processes, was significantly upregulated in EM-AML. To test the functional impact of TWIST1 overexpression, we treated OCI-AML3s with TWIST1-siRNA or metformin, a drug known to inhibit tumor progression in cancer models. After 48 h, we showed downregulation of TWIST1, and of the EMT-related genes FN1 and SNAI2. This was associated with significant impairment of migration and invasion processes by Boyden chamber assays. Our study shed light on the molecular mechanisms associated with EM tissue invasion in AML, and on the ability of metformin to interfere with key players of this process. TWIST1 may configure as candidate marker of EM-AML progression, and inhibition of EMT-pathways may represent an innovative therapeutic intervention to prevent or treat this complication.

Intradural extra medullary spinal tumours – An urban institute’s experience

BackgroundIntradural Extra Medullary tumours consists of 70% of all spine tumours. The present study analyses the clinical presentation, prognostic factors, radiological assessment, treatment, histological examination and their correlation with outcome of these spinal tumors, in an urban setup of India. The study presents our single institution’s surgical experience and clinical outcomes on patients who have undergone surgical excision for intradural spinal tumors. MethodologyThis retrospective and prospective observational study was conducted among 104 patients admitted in an Institute of Higher Education and Research, Chennai between 2011 and 2022. All patients were clinically evaluated along with preoperative and post operative modified Nurick grading with 6 months of follow up. Statistical analysis was performed using SPSS. ResultsOur study included 104 patients, mean age was 40.43 years. Of the participants, 64 (61.5%) were men and the remaining 40 were women. The mean duration of presentation was 9.3 months (1±120 months). Motor Weakness was the most common symptom noted in 69 patients. The tumors were commonly seen in thoracic region − 43 cases (41.3%). Schwannoma was the commonest lesion and there was a male preponderance. ConclusionOur study clearly demonstrates that surgical treatment of an IDEM offers very good functional outcomes irrespective of the age of the patient or the neurological status. Hence surgery should be offered to all patients presenting with an IDEM.

Venetoclax durable response in adult relapsed/refractory Philadelphia-negative acute lymphoblastic leukemia with JAK/STAT pathway alterations.

High-risk relapsed/refractory adult Philadelphia-negative (Ph-) B-cell acute lymphoblastic leukemia (B-ALL) is a great challenge due to limited possibilities to achieve and maintain a complete response. This also applies to cases with extramedullary (EM) involvement that have poor outcomes and no accepted standard therapeutic approaches. The incidence of EM localization in relapsed/refractory B-ALL is poorly investigated: data on patients treated with blinatumomab reported a 40% rate. Some responses were reported in EM patients with relapsed/refractory B-ALL treated with inotuzumab ozogamicin or CAR-T. However, molecular mechanisms of response or refractoriness are usually investigated neither at the medullary nor at EM sites. In the complex scenario of pluri-relapsed/refractory B-ALL patients, new target therapies are needed. Our analysis started with the case of an adult pluri-relapsed Ph- B-ALL patient, poorly sensitive to inotuzumab ozogamicin, donor lymphocyte infusions, and blinatumomab in EM disease, who achieved a durable/complete response after treatment with the BCL2-inhibitor venetoclax. The molecular characterization of medullary and EM samples revealed a tyrosine kinase domain JAK1 mutation in the bone marrow and EM samples at relapse. By comparing the expression level of BCL2- and JAK/STAT pathway-related genes between the patient samples, 136 adult JAK1 wt B-ALL, and 15 healthy controls, we identified differentially expressed genes, including LIFR, MTOR, SOCS1/2, and BCL2/BCL2L1, that are variably modulated at diverse time points and might explain the prolonged response to venetoclax (particularly in the EM site, which was only partially affected by previous therapies). Our results suggest that the deep molecular characterization of both medullary and EM samples is fundamental to identifying effective and personalized targeted therapies.

Extramedullary involvement in pediatric myeloid leukemia: challenges of diagnosis and treatment. Clinical cases and a literature review

The problem of extramedullary (EM) involvement in acute myeloid leukemia (AML) in children is of considerable relevance since its pathogenesis remains understudied and the impact on prognosis is still unclear. The variability of tissue and organ involvement depends on immunophenotypic, cytogenetic, and molecular features of myeloid cells and can cause difficulties in diagnosis, thus making it necessary to combine imaging and laboratory tools for timely and accurate diagnosis of EM disease. The prognostic significance of EM involvement has not been established unequivocally, thus the need for intensification of chemotherapy, as well as for allogeneic hematopoietic stem cell transplantation in first remission, remain debatable. The results of target therapy in EM AML are encouraging and may reduce the risk of AML relapse. This article describes the clinical features of EM AML in children and reviews the diagnostic approaches as well as the advantages and limitations of existing laboratory and imaging methods. The molecular features of EM AML, current treatment options and prognosis have also been analyzed. The patients' parents gave their consent to the use of their children's data, including photographs, for research purposes and in publications.

Isolated Intra-Oral Relapsed B-Acute Lymphoblastic Leukemia (B-ALL): A Case Report

B-Lymphoblastic Leukemia (B-ALL) is the second most common acute leukemia in adults. Its clinical manifestations include leukocytosis or leukopenia, anemia, and thrombocytopenia with an overall poor prognosis in elderly patients. If relapse occurs, it commonly involves the bone marrow but can also involve Extramedullary (EM) sites such as the brain, testis, liver, spleen and lymph nodes. Isolated extramedullary involvement of the oral cavity in relapse B-ALL is extremely rare with only a few reposted cases in the literature in pediatrics and Adolescent-and-Young-Adult (AYA) population. Here we describe the case of an elderly gentleman who presented with isolated EM B-ALL relapse involving the oral cavity and gnathic bones which was initially misdiagnosed as an odontogenic infection.

The Effect of Intramedullary vs Extramedullary Tibial Guides on the Alignment of Lower Extremity and Functional Outcomes Following Total Knee Arthroplasty: A Randomized Clinical Trial.

Total knee arthroplasty (TKA) has been known as a definitive treatment for advanced knee osteoarthritis. Both intramedullary (IM) and extramedullary (EM) tibial guides have been used to restore the desired extremity alignment. However, controversy exists regarding the superiority of either technique We aimed to compare the functional outcomes and accuracy of IM and EM tibial guides in providing neutral alignment after TKA. In a randomized, double-blinded clinical trial, we studied 98 patients undergoing primary TKA in two groups of IM and EM. We measured the medial proximal tibial angle (MPTA), varus angle (VA), and joint-line convergence angle with normal ranges of 90°±3°, 0-2°, and 0±3°, respectively, on a three-joint alignment view after three months. We also assessed the functional outcomes at the last follow-up. Finally, we compared these outcomes between the two groups. Eighty-four patients (IM=42, EM=42) were included in the final analysis (16 males, 68 females, mean age: 63.9±8.6 years, mean follow-up: 13±2.9 months). The mean postoperative (post-op) alignment angles showed no significant difference, although MPTA outliers were significantly more frequent in the EM group (26.2% vs. 9.5% in IM, P=0.04). None of the functional outcomes showed a significant difference between the two groups. However, the mean increase in knee range of motion (ROM) was significantly higher in the knees with VAs within ±3° of neutral than those outside this range (30.8 vs. 27.4, respectively, P=0.039). We conclude that both techniques were not different regarding the mean alignment angles and functional outcomes. However, fewer MPTA outliers can be seen with the IM technique. A post-op mechanical axis within ±3° of neutral can result in a more ROM increase after one year.

Improved Survival of Adolescents and Young Adults (AYA) Patients Aged 14-40 Years with First Relapse of Acute Lymphoblastic Leukemia Using Pediatric-Inspired Chemotherapy Salvage Protocol (R3 induction protocol)

Background: Although survival of adolescent and young adults (AYA) with acute lymphoblastic leukemia (ALL) has improved using pediatric-inspired protocols, the outcomes of those who relapse remain poor using adult chemotherapy salvage-regimens that have historically incorporated high dose Ara-C based regimen, with long term-survival of less than 10%. The CR rate with blinatumomab for salvage in adult ALL is 34% with a median survival of 7.7 months, with an OS of less than 30% at 18 months. In contrast, pediatric salvage regimens have historically been based on multi-agent therapy and have reported superior outcomes. The ALLR3 protocol for relapsed ALL in patients up to the age of 18 years reported a CR rate of 97% and an overall survival of 72%. We therefore aimed to analyze the outcomes of young adolescents and adults treated on the R3 regimen +/- blinatumomab. Methods: Seventeen AYA patients with Philadelphia-negative ALL aged between 14 and 40 years who relapsed after first-line therapy and treated with ALLR3-protocol were identified. Relapses were classed as very early (<18 months from diagnosis) early (>18m from diagnosis and <6 months from end of therapy) and late (>6 months from end of therapy). The protocol consisted of vincristine (1.5mg/m2 IV D3,10,17,24); mitoxantrone ( 10mg/m2 IV d1 &2); PEG-asparaginase (1000 u/m2 IV d3 & 17); dexamethasone (10mg/m2 BID day d1-5 and d15-20); and intrathecal methotrexate (12mg d1 & d8) were identified. Patient aged 30-40 years received L-Asparaginase instead of PEG-Asparaginase, and 8mg/m2 of dexamethasone instead of 10mg/m2. Patients' characteristics, response rate (RR) and overall survival (OS) were analyzed. Patients who achieved minimal residual disease (MRD) negative CR proceeded with an allogeneic transplant. MRD-positive patients received blinatumomab followed by a transplant. Results: The median age at relapse was 16 years (14-40 years), 88.2% of patients were B-cell ALL and 11.8% were T-cell ALL. Most patient had standard cytogenetics on presentation (76.5%) and were CNS negative (82.4%). Relapses were very early, early or late in 2 (12%) , 5 (29%) , and 7 (41%) of cases, respectively. Relapses were isolated bone marrow (BM), isolated extramedullary (EMD) or combined BM and EMD in 14 (82%),1 (6%) and 2(12%) cases, respectively. Overall complete remission (CR) rate was 60% at the end of R3 induction; CR with negative minimal residual disease (MRD negative, <10−4 cells) at the end of R3-induction was achieved in 47.1% of patients, while 11.8% of patients had CR with positive MRD (≥10−4 cells) who received Blinatumumab thereafter with eradication of MRD. Refractory disease was seen in 41.2% of patients. Almost all patients who responded to R3 proceeded to allogeneic stem cell transplant (88.8%). Eight patients died (47%), but only one patient died because of treatment-related sepsis, while the other 7 patients died because of disease-related causes. At a median follow up of 4 years, OS was 47.3%. Conclusion: Compared to traditional adult-based chemotherapy regimens and antibody therapies used in relapsed ALL, the use of pediatric-inspired protocol (R3) in relapsed AYA-ALL patients showed favorable response rates and overall survival. Further trials are required of pediatric inspired salvage regimens, preferably incorporating antibody therapies in adult patients, especially in 1st relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Enhanced Global Disease Assessment with Advanced Imaging and Targeted Myeloma Lesion Biopsy Highlights Spatial Heterogeneity and Detects Residual Disease in Multiple Myeloma

Background: Multiple myeloma (MM) is a biologically complex disease with marked heterogeneity; limitations remain in our standard myeloma disease assessment at diagnosis and in response to therapy. In this study, we aimed to prospectively investigate the utilization of advanced imaging and targeted focal lesion (FL) biopsies to augment global disease evaluation, detect residual tumor burden, and explore the diverse histologic and molecular landscape of this multifocal neoplasm. Herein, we present our final analysis of this clinical trial. Methods: Adult patients with newly diagnosed clinical MM (NDMM) and bone or extramedullary (EM) FL were eligible to participate in this prospective study. Advanced imaging with positron emission tomography/computed tomography (PET/CT) or whole body magnetic resonance imaging (WB-MRI), standard bone marrow (BM) biopsy and aspiration, and targeted FL biopsy were performed at enrollment and after four 28-day cycles of induction therapy with carfilzomib (36 mg/m2 intravenously twice weekly), lenalidomide (25 mg orally days 1-21), and dexamethasone (40 mg orally weekly) (KRd), with dose modifications as needed. Conventional clinical response, using IMWG Response Criteria (Kumar S et al, 2016), was also measured after each cycle of treatment. Patients were followed for 12 months after end of treatment or until data cutoff on February 23rd, 2022. Results: 27 patients were enrolled in this study between June 2018 and August 2021, with 25 evaluable for global response assessment. Median age was 61 years (range, 42-76 years) and 14.8% of patients were of Black or African American race. 85.2% of patients had Revised International Staging System (R-ISS) stage II or III disease. 51.9% of patients were identified as having EM disease arising out of bone or soft tissue and 44.4% of patients had high risk cytogenetics inclusive of chromosome 1 abnormalities. In sum, 70.4% of our cohort had at least 1 high risk feature at diagnosis (Table 1). 80% of patients had myeloma FL identified on advanced imaging that were missed on conventional skeletal survey. Of the 7 patients with cytogenetic and fluorescence in situ hybridization (FISH) testing performed on initial FL biopsy, 6 (85.7%) had findings discrepant from those seen on cytogenetic testing from standard BM samples. 9 patients had cytogenetic and FISH studies on repeat myeloma FL biopsy after KRd induction with 2 showing residual FISH abnormalities that were not detected on standard BM obtained for response assessment. Clinical response rates after 4 cycles of KRd were high in our study population with 88% of patients achieving a very good partial response (VGPR) or better and 20% with a stringent complete response (sCR) with minimal residual disease (MRD) negativity by flow cytometry. However, of the 22 patients with ≥VGPR by IMWG response assessment, 18 had residual disease on advanced imaging with WB-MRI (10 patients), PET/CT (7 patients), or MRI total spine (1 patient), including 3 of the 5 patients with sCR (Figure 1). 2 patients experienced disease progression during the study period with median progression free survival not reached by the patient cohort. Both patients with progression had a VGPR by conventional response assessment, though with residual FL on advanced imaging post-KRd induction. Conclusions: While tumor spatial differences in MM have been observed retrospectively, prospective data on this important component of myelomagenesis is limited. In our cohort of high risk NDMM, we demonstrated spatial heterogeneity both at diagnosis and after KRd induction. Despite the deep clinical responses observed by IMWG response assessment, 81.8% of patients with ≥VGPR had ongoing abnormalities on advanced imaging which could potentially serve as disease reservoirs for future progression and development of treatment resistance. A novel assessment method in MM, inclusive of advanced imaging and targeted FL biopsies, may overcome the limitations of our standard response assessment with resultant improved knowledge of the varied intra-tumor disease biology as well as development of more refined treatment approaches. A potential limitation of our study is the smaller sample size with underrepresentation of minority populations. Data on whole exome sequencing of paired BM and FL biopsies will be reported separately. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Role of radiotherapy in treatment of extramedullary relapse following total marrow and lymphoid irradiation in high-risk and/or relapsed/refractory acute leukemia.

Total Marrow and Lymphoid Irradiation (TMLI) is a promising component of the preparative regimen for hematopoietic cell transplantation in patients with high-risk acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Extramedullary (EM) relapse after TMLI is comparable to TBI and non-TBI conditioning regimens. This study evaluates outcomes of patients treated with radiotherapy (RT) with EM relapse previously treated with TMLI. A retrospective analysis of five prospective TMLI trials was performed. TMLI targeted bones and major lymphoid tissues using image-guided tomotherapy, with total dose ranging from 12 to 20 Gy. EM recurrences were treated at the discretion of the hematologist and radiation oncologist using RT ± chemotherapy. Descriptive statistics and survival analysis were then performed on this cohort. In total, 254 patients with refractory or relapsed AML or ALL were treated with TMLI at our institution. Twenty-one patients were identified as receiving at least one subsequent course of radiation. A total of 67 relapse sites (median=2 sites/patient, range=1-16) were treated. Eleven relapsed patients were initially treated with curative intent. Following the initial course of subsequent RT, 1-year, 3-year and 5-year estimates of OS were 47.6%, 32.7% and 16.3%, respectively. OS was significantly better in patients treated with curative intent, with median OS of 50.7 months vs 1.6 months (p<0.001). 1-year, 3-year and 5-year estimates of PFS were 23.8%, 14.3% and 14.3%, respectively. PFS was significantly better in patients treated with curative intent, with median PFS of 6.6 months vs 1.3 months (p<0.001). Following RT, 86.6% of the sites had durable local control. RT is an effective modality to treat EM relapse in patients with acute leukemia who relapse after HCT achieving high levels of local control. In patients with limited relapse amenable to curative intent, radiation confers favorable long-term survival. Radiation as salvage treatment for EM relapse after HCT warrants further evaluation.

Expression of Twist 1 in bone marrow and extramedullary lesions of patients with myeloma and its prognostic significance

In patients with multiple myeloma (MM) extramedullary (EM) lesions could be a possible indicator of poor prognosis. Twist 1, an EMT related transcription factor, is known to play an important role in embryonic development and also in the process of tumor cell proliferation, apoptosis, metastasis etc. The Twist 1 protein expression hence has prognostic significance in MM. This study investigates expression of Twist-1 in MM patients with extramedullary lesions and its relationship with clinicopathological data and prognosis, so as to elucidate the clinical significance of Twist-1 expression. Patients with MM complicated with EM lesions were selected retrospectively, including 35 cases in the bone marrow group (MM complicated with extramedullary lesions) and 80 cases in the extramedullary group (MM combined with extramedullary lesions). The expression of Twist 1 protein was detected by immunohistochemistry. The relationship between Twist 1 protein expression and general clinicopathological data was analyzed by statistics. The relationship between Twist 1 protein expression and prognosis was analyzed by COX single factor and multivariate regression analysis. Immunohistochemical staining showed that the expression level of Twist-1 protein in the nucleus of myeloma cells in the extramedullary group was significantly higher than that of the bone marrow group. However, in the cytoplasm of myeloma cells, there was no significant difference in the expression level of Twist-1 protein between the extramedullary group and the bone marrow group. The expression level of Twist-1 protein in extramedullary tissue was not related to sex, age, D-S stage, ISS stage, immunoglobulin type, creatinine and hemoglobin. The expression level of β2-microglobulin in Twist-1 high expression group was significantly higher than that of Twist-1 low expression group. Follow-up findings discovered that overall survival (OS) of Twist 1 high expression group was significantly lower than that of Twist 1 low expression group. COX multivariate analysis showed that Twist 1 protein and International Staging System (ISS) stage were independent risk factors affecting OS for 3 years. The high expression rate of Twist 1 protein in extramedullary lesions of MM patients with extramedullary lesions is significantly higher than that in bone marrow tissues of patients with extramedullary lesions. The results suggest that high expression of Twist 1 protein is an independent risk factor affecting the prognosis of MM patients with extramedullary lesions.