Omer, Zulfa

Abstract Introduction: Clinical outcomes for patients (pts) with Philadelphia chromosome positive (Ph+) B-cell precursor Acute Lymphoblastic Leukemia (B-ALL) have significantly improved with the incorporation of tyrosine kinase inhibitors (TKI) and immunotherapy. Although the incidence of central nervous system (CNS) relapse in Ph+ B-ALL is rare, it has become an emerging challenge with chemotherapy-free approaches. While IKZF1, CDKN2A/B and emergence of T315I kinase domain mutations in ABL1 have been associated with worse outcomes (Foà R, JCO, 2024),further characterization of patients with CNS relapse could prove useful in risk stratification and optimizing treatment intensification. Currently, high white blood cell count (WBC) is being assessed as a marker to identify pts who may benefit from addition of CNS penetrant chemotherapy (ex. cytarabine or high-dose methotrexate (HD-MTX)) to TKI and immunotherapy protocols (Short NJ, J Hematol Oncol, 2025). Methods This is a multicenter retrospective study of relapsed/refractory Ph+ B-ALL pts under the COMMAND consortium. Age, gender, induction regimen and TKI of choice during induction were descriptively reported for the entire cohort. Categorical variables were compared, using Fisher's exact test, between pts with CNS relapse and pts with systemic relapse. Variables of interest were the presence of IKZF1 or CDKN2A/B alterations, emergence of T3151 mutation, CNS disease at diagnosis (dx), WBC >70K/microliter at dx, use of high-dose methotrexate (HD-MTX) during induction or consolidation, and use of TKI as part of the induction regimen. Odds ratio (OR) and 95% confidence intervals (CI) were reported for each variable. Results A total of 654 Ph+ B-ALL pts were initially identified across multiple centers in the United States, of whom 20 (3%) experienced a CNS relapse and 157 (24%) experienced a systemic relapse on median follow up of 29 months (range, 0-207). A total of 15 pts with CNS relapse and 114 pts with systemic relapse were used for this analysis after exclusion of pts without molecular data. The median age for the 129 pt cohort was 55 years (range 22-85), of whom 65 pts (50%) were male. Induction regimens used were intensive chemotherapy (IC)+TKI for 79 pts (61%), low-intensity chemotherapy or steroids (LDC-S)+TKI for 40 pts (31%), IC without TKI during induction for 5 pts (4%) and blinatumomab+TKI for 1 pt (1%). TKI of choice during induction included second-generation TKIs (dasatinib, nilotinib) for 77 pts (60%), imatinib for 30 pts (23%), ponatinib for 15 pts (12%) and none during induction for 5 pts (4%). CNS disease at dx was found in 6/15 pts (40%) with CNS relapse and 9/114 pts (8%) with systemic relapse, which was a statistically significant difference (p=0.002, OR= 7.57, 95% CI= 1.81 - 31.08). The systemic treatment regimens for the 15 pts with CNS disease at x were IC+TKI for 10 pts (66%) and LDC-S+TKI for 5 pts (33%), 9 of the pts (60%) received HD-MTX during induction. Intrathecal (IT) chemotherapy administration data at dx was available for 8 pts (53%) with CNS disease at dx, of whom 2 pts received <9 doses, 4 pts received 9-12 doses and 2 pts received >12 doses of IT chemotherapy. Although not statistically significant, pts with CNS relapse were more likely to have IKZF1 or CDKN2A/B alterations (p = 0.648, OR= 1.44, 95% CI= 0.14-7.78), WBC >70K/mcl (p = 0.472, OR= 1.73, 95% CI= 0.34-7.41), emergence of T3151 mutations (p = 0.123, OR= 2.54, 95% CI= 0.72-8.84) and use of HD-MTX during induction or consolidation (p = 0.262, OR= 2.15, 95% CI= 0.61-8.61); while they were less likely to have received a TKI during induction (p = 0.106, OR= 0.18, 95% CI= 0.02-2.34). Conclusion This data confirms that the presence of CNS disease at dx is associated with CNS relapse. Despite recent incorporation into clinical trials, WBC≥70K/mcl and omission of HD-MTX were not seen more frequently in pts with CNS relapse in this cohort. However, this analysis is limited by the small number of pts who experienced CNS relapse. With the rising use of chemotherapy-free regimens, prospectively trialing treatment intensification, such as with additional IT chemotherapy or HD-MTX, could be prospectively trialed in pts with CNS disease at dx to potentially improve outcomes for this subset of pts. The impact of increasing IT chemotherapy doses or additional cycles of systemic chemotherapy in this pt population is yet to be elucidated.

Abstract Background: Given a potential risk of extravasation with vesicants and irritants, central venous catheters (CVCs), such as port-a-cath or peripherally inserted central catheters (PICC), are commonly used for the administration of anthracycline-based chemotherapy. However, CVC placement can result in treatment delay, deep vein thrombosis (DVT), catheter malfunction, and added burdens (eg, financial, travel, etc), partly due to the need for regular flushing. Peripheral intravenous (PIV) access is often utilized in the academic setting with select frontline chemotherapy regimens. However, there is limited data reporting on the safety of PIV in this setting. This large, multicenter RWA evaluated the use and associated complications of PIV and CVC for administering CHOP- or ABVD-based chemotherapy in patients (pts) with lymphoma. Methods: We conducted a retrospective RWA across 8 U.S. centers among pts aged ≥18 years with non-Hodgkin lymphoma and Hodgkin lymphoma who were consecutively treated with ABVD or CHOP-based anthracycline chemotherapy via PIV or CVC access between 2010-2024. Choice of catheter placement was at the discretion of the pt's treating physician. Detailed baseline and safety data were collected. The primary outcome was extravasation; secondary outcomes included infiltration, DVT, cellulitis, erythema, and pain. Standard definitions of extravasation and other complications were used (Jackson-Rose J. CJON 2017). Rates of complications were compared via Fischer exact testing. Results: A total of 1,414 pts were included in the analysis: 790 in each arm (ie, PIV vs CVC). Of these, 624 were unique to each group, while 166 pts received chemotherapy via both modalities (PIV and CVC during the treatment course). Overall, 78.9% of pts completed all treatment as planned via PIV. Median age was 63 years (IQR 45–75) in the PIV group and 61 years (IQR 40–73) in the CVC group. Male sex comprised 57% vs 51%, ECOG 0–1 performance status was 83% vs 76%, and advanced-stage disease (stage III/IV) was present in 51% vs 62%, respectively. Lymphoma subtypes were comparable: DLBCL/high-grade/B-cell NOS (54.5% vs 56.1%), Hodgkin lymphoma (27.2% vs 27.5%), T-cell lymphoma (12.4% vs 6.6%), and indolent/mantle cell lymphoma (5.6% vs 6.7%). Among those receiving chemotherapy via CVC, 78.5% were treated through a port-a-cath and 21.5% via PICC. CHOP-based and ABVD-based regimens were administered to 68% and 32% of PIV pts, and 69.6% and 30.4% of CVC pts, respectively. A total of 4,084 (PIV) vs 3,859 (CVC) treatment cycles were delivered, corresponding to 4,347 (PIV) vs 4,884 (CVC) anthracycline infusion days. There was 1 documented case of extravasation in the CVC group and 2 suspected cases in the PIV group (p=0.9); for PIV, this translates to a per pt risk of 0.3% (or 0.05% of infusion days). The two PIV cases involved elderly women with DLBCL receiving CHOP. Both developed localized symptoms post-infusion and were treated conservatively (DMSO/warm compresses or dexrazoxane/ice), with full symptom resolution within 1 week and 1 day, respectively. No tissue or vascular injury occurred. Additionally, there were no significant differences between the PIV and CVC groups in the rates of induration/swelling (1.8% vs 2.0%, p=0.85), phlebitis/cellulitis (2.4% vs 2.4%, p=0.9), venous thromboembolism (VTE; 1.4% vs 2.0%, p=0.32), or erythema (3.8% vs 5.1%, p=0.27). Pain or tenderness at the infusion site (8.5% vs 2.9%, p=0.001) and infiltration (1.4 vs 0.13%, p=0.006) were more frequent in the PIV group. Chronic vascular complications related to prior VTE was slightly lower in the PIV group (0.13% vs 0.9%, p=0.06), but not significant. Additional details from a propensity score-matched analysis will be presented at the meeting. Conclusions: This is the largest known analysis to date evaluating the safety of PIV access for anthracycline-based chemotherapy in >1,500 lymphoma pts over a recent 15-year period, representing >9,000 total treatments with CHOP or ABVD. PIV access was found to be safe and associated with a low rate of serious complications. Moreover, extravasation was rare and there was not a significant difference observed between PIV and CVC use. While PIV use was associated with higher rates of local pain/tenderness and infiltration, the events were uncommon and self-limited. Despite the widespread default to CVC placement in many centers, these findings support the selective use of PIV in appropriate pts as elucidated here.

Introduction: Complex karyotype (CK, ≥3 chromosome (chr) abnormalities (abn)) is an important adverse prognostic indicator in chronic lymphocytic leukemia (CLL). CK at diagnosis (dx) of CLL, particularly with major structural chr abn (i.e. unbalanced translocation, add, marker, ring chr), called type-2 CK (CK2), has been associated with an increased risk of Richter transformation (RT) (Visentin Haematologica 2022). RT is defined as development of aggressive lymphoma, most often large B-cell lymphoma, in the setting of CLL. In patients (pts) with relapsed/refractory CLL treated with ibrutinib, CK as a continuous variable and the presence of polyploidy were independent predictors for RT. CK is a common finding at the time of RT, and high-CK (≥5) has been associated with short survival in RT, although previous studies predominantly included pts with prior chemoimmunotherapy (CIT) administration for their CLL. The prognostic significance of CK in pts with RT whose prior CLL-directed therapies include only non-CIT, as is the current standard of care for CLL, has not been evaluated. Methods: We conducted a multicenter, retrospective analysis of pts from 14 academic centers. Pts with RT diagnosed between 6/2011 to 6/2023, who had CLL-directed treatment that did not include prior CIT, with stimulated karyotype data available, were included. Pts who did not receive treatment for their CLL prior to developing RT were not included. Baseline pt, disease, and cytogenetics data were collected via chart review at time of CLL diagnosis and at the development of RT. Karyotype abn up to 20 were counted on both CLL tissue (peripheral blood or bone marrow) and RT tissue using IWGMC guidelines (Chun Leuk Res 2010). CK was categorized as CK1 (balanced abn, deletion, aneusomies) or CK2. Polyploidy was defined as ≥58 chrs. Karyotype was considered evolved if one or more chr abn were seen in a follow-up sample of CLL tissue that were not seen at CLL dx.TP53 disruption was defined as presence of del(17p) or TP53 mutation. Overall survival (OS) was measured from RT dx and estimated using the Kaplan-Meier method. Cox regression model was used to identify prognostic factors associated with OS. Results: A total of 64 eligible pts were identified. Median age at RT dx was 65 years (range 40-89) and 71.9% of pts were male. Of those evaluated (n=49), 79.6% had unmutated IGVH. Median number of therapies for CLL prior to RT was 1 (range 1-5) and included BTK inhibitor (n=37), BCL2 inhibitor (n=3), both (n=18), or other non-CIT treatment (n=6). At CLL diagnosis, 54.7% of pts had a CK, and the median number of chr abn was 3 (range 0-20). Of those with CK, 96.9% had a CK2, and 6.3% had a polyploid subclone. TP53 disruption was found in 46% of pts. At time of RT, chr analysis of CLL tissue was available for 38 pts and showed 78.9% had a CK, and the median number of chr abn was 8 (range 0-20). Polyploidy was found in 29.6%. TP53 disruption (46 pts evaluated) was found in 52.2%. Karyotype evolution from dx (35 pts evaluated) occurred in 74.3% of pts. In RT tissue, of those evaluated (n=29), 96.6% were clonally related to the preceding CLL. MYC translocation (45 pts evaluated) occurred in 17.8%. CK (20 pts evaluated) was found in 70%, with a median number of chr abn of 8 (range 0-20). Of those with CK, 33.3% had a polyploid subclone. With a median follow-up of 17.8 months (range 2.1-83.0) there were 42 deaths, with a median OS of 14.3 months (range 6.9-29.1). For this subset of patients with karyotype data available who would go on to develop RT, an exploratory univariable analysis for OS from RT found that increasing number of chr abn as a continuous variable at CLL dx was associated with worse OS (HR 1.10, 95% CI 1.02-1.19, p=0.01). Similarly, at RT, increasing number of chr abn in CLL tissue (HR 1.09, 95% CI 1.02-1.16, p=0.01) and in RT tissue (HR 1.09, 95% CI 1.01-1.18, p=0.03) was also prognostic of survival. Karyotype evolution in CLL tissue at RT (HR 3.02, 95% CI 1.02-8.94, p=0.05) was borderline significant for worse OS. Conclusions: Our multi-center study identified increasing number of chr abn at CLL diagnosis and at time of RT, and clonal evolution in the CLL tissue, are associated with worse OS in pts with RT whose CLL was treated without CIT. Limitations include incomplete cytogenetics data across the cohort and potential variability across institutions in cytogenetics laboratory practices. This provides further evidence for the clinical utility of chr analysis in the modern era of CLL therapy.

Background While central nervous system (CNS) disease is found in minority of patients (pts) at diagnosis of Ph+ ALL, later relapses can occur in pts despite adequate CNS prophylaxis. CNS disease can be managed with varying combinations of systemic, radiation, and intrathecal (IT) therapy and can be associated with significant toxicity, especially in older pts. While there are more durable systemic responses with 2nd or 3rd generation tyrosine kinase inhibitors (TKIs) based combinations, CNS penetration can vary by TKI. In this large multi-center study, we analyze the incidence of CNS disease in Ph+ ALL in the context of induction therapies and survival post relapse. Methods We conducted a multicenter observational study in collaboration with 10 U.S. academic centers under the COMMAND consortium and reviewed the incidence of CNS relapse in 505 Ph+ ALL pts. We evaluated baseline characteristics, treatment given prior to CNS relapse, and outcome post relapse. Results Baseline characteristics, initial treatment and outcome prior to CNS relapse Eighteen (3.56%) pts were identified to have CNS disease at relapse. Median age of the pts in years (yrs) was 51 (range [R], 22-75), median white blood cell (WBC) was 33.3 x 10(9)/L (R, 2.1-200) and 6 (33%) pts had additional cytogenetic abnormalities at diagnosis. Sixty-one percent (n= 11) of pts received intensive chemotherapy (IC) during induction; 2 (11%), 14 (78%) and 2(11%) of pts received 1st, 2nd or 3rd generation TKI-based combination during induction, respectively. All of pts achieved complete remission (CR), 45.5% achieved complete molecular remission (CMR) at 3 months from the time of diagnosis. Five (28%) pts received allogeneic stem cell transplantation (allo-HCT) as a consolidation therapy. Treatment received at CNS relapse and response The median time to CNS relapse after induction was 10.8 months (mo) (R, 2-79). All pts except 1 had isolated CNS relapse after CR1, 4/18 (22%) pts had T315I mutation at relapse. Twelve (67%) and 6 (33%) pts received intrathecal chemotherapy (IT) with TKI and systemic chemotherapy + TKI in addition to IT, respectively. Eleven (61%) pts received dasatinib, 5 (28%) pts received ponatinib and one (6%) pts each received bosutinib and imatinib at relapse. Ninety-three percent of pts achieved CR (n=3, not evaluable). Six (33%) pts underwent allo-HCT after CNS relapse, one of these transplanted pts had second allo-HCT. Survival after CNS relapse The median relapse free survival (RFS) and overall survival (OS) after CNS relapse was 9.8 (95% CI: 3.80-15.76) and 13.87 (95% CI: 4.08-23.65) mo, respectively. In subset analysis, we compared survival outcome among pts who had relapse without CNS involvement (n= 160/505 [32%]). The median RFS (9.9 vs 9.8, p= 0.88) and OS (31.53 vs 28.80, p= 0.57) after relapse was not significantly different among pts who had relapse with or without CNS involvement, respectively. We also compared OS among pts without relapse to those with relapse. The median OS was not reached (NR; 73% alive at 5 years), 28.80 and 31.53 months (p= <0.001) among pts with no relapse, relapse with CNS and without CNS involvement, respectively. Conclusion Our retrospective analysis from a large database showed that CNS relapses were uncommon (3.56%) in adult pts with Ph+ ALL. A majority of pts (89%) received a 2nd or a 3rd generation TKI during induction. Approximately one quarter of pts with CNS relapse had emergence of T315I mutation. While almost all pts achieved CR, the RFS was relatively short. We did not see significant differences in survival among pts who had relapse with or without CNS involvement.