Lekha Mikkilineni

All Publications

• A 17-Year Experience of a Large Dedicated Fellowship in Blood and Marrow Transplantation and Cellular Therapy: A Blueprint for Modern Day Training Program. Journal of cancer education : the official journal of the American Association for Cancer Education Bharadwaj, S., Lowsky, R., Mikkilineni, L., Smith, M., Weng, W. K. 2024

  Abstract

  The field of allogeneic blood and marrow transplantation-cellular therapy (BMT-CT) has evolved through incremental advances. Engineered donor grafts, gene editing and chimeric antigen receptor T-cells are all standard clinical practice. Consequently, the scientific knowledge and complexity of clinical skills needed for next generation of BMT-CT physicians have increased. We report a 17-year experience of arguably the largest 12-month BMT-CT clinical fellowship program in the USA. Seventy-three (73) trainees were accepted and 2 cohorts that reflected different time periods (2007-1016 and 2017-2024, inclusive) and different core training curriculum were compared. The cohorts were equivalent in terms of demographics; notably, most (70%) had graduated from international medical schools and trained in the US on a non-immigrant J1 visa. In 2015, we introduced a structured mentoring program to address the desire of trainees for experience with scholarly activities. There was a high rate of successful academic careers with a trend toward a higher likelihood of academic retention following structured mentoring (70% vs 89%). In this report, we included our detailed core curriculum and highlight potential future changes as a blueprint for modern day programs to ensure that graduate "transplant docs" can continue to contribute at the highest academic level.

  View details for DOI 10.1007/s13187-024-02545-3

  View details for PubMedID 39604772

  View details for PubMedCentralID 9947862

• Immune effector cell-associated enterocolitis following chimeric antigen receptor T-cell therapy in multiple myeloma. Blood cancer journal Fortuna, G. G., Banerjee, R., Savid-Frontera, C., Song, J., Morán-Segura, C. M., Nguyen, J. V., Lekakis, L., Fernandez-Pol, S., Samraj, A. N., Naresh, K. N., Vazquez-Martinez, M., Baz, R. C., Spiegel, J. Y., Mikkilineni, L., Gubatan, J. M., Sidana, S., de Menezes Silva Corraes, A., Kalariya, N. M., Patel, K. K., Shim, K. G., Fonseca, R., Ferreri, C., Voorhees, P. M., Richard, S., Valdes, C. R., Wolf, J. L., Cowan, A. J., Sborov, D. W., Locke, F. L., Lin, Y., Wang, Y., Hansen, D. K. 2024; 14 (1): 180

  Abstract

  We report 14 cases of immune effector cell (IEC)-associated enterocolitis following chimeric antigen receptor T-cell (CAR-T) therapy in multiple myeloma, with a 1.2% incidence overall (0.2% for idecabtagene vicleucel and 2.2% for ciltacabtagene autoleucel). Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 92.5 days (range: 22-210 days) after CAR-T therapy and a median of 85 days after cytokine release syndrome resolution. Gut biopsies uniformly demonstrated inflammation, including intra-epithelial lymphocytosis and villous blunting. In one case where CAR-specific immunofluorescence stains were available, CAR T-cell presence was confirmed within the lamina propria. Systemic corticosteroids were initiated in 10 patients (71%) a median of 25.5 days following symptom onset, with symptom improvement in 40%. Subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. Five patients (36%) have died from bowel perforation or treatment-emergent sepsis. In conclusion, IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy typically beginning 1-3 months after infusion. Thorough diagnostic workup is essential, including evaluation for potential T-cell malignancies. The early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.

  View details for DOI 10.1038/s41408-024-01167-8

  View details for PubMedID 39414769

  View details for PubMedCentralID 8873238

• Safety and Efficacy of Standard of Care Ciltacabtagene Autoleucel for Relapsed/Refractory Multiple Myeloma. Blood Sidana, S., Patel, K. K., Peres, L. C., Bansal, R., Kocoglu, M. H., Shune, L., Atrash, S., Smith, K., Midha, S., Ferreri, C. J., Dhakal, B., Dima, D., Costello, P., Wagner, C., Reshef, R., Hosoya, H., Mikkilineni, L., Atanackovic, D., Chhabra, S., Parrondo, R. D., Nadeem, O., Mann, H., Kalariya, N., Hovanky, V., DeAvila, G., Freeman, C. L., Locke, F. L., Alsina, M., Wong, S., Herr, M. M., Htut, M., McGuirk, J. P., Sborov, D. W., Khouri, J., Martin, T., Janakiram, M., Lin, Y., Hansen, D. K. 2024

  Abstract

  Ciltacabtagene autoleucel (cilta-cel) CAR-T therapy was approved in 2022 for patients with relapsed/refractory multiple myeloma (RRMM). We report outcomes with cilta-cel in the standard-of-care setting. Patients with RRMM who underwent leukapheresis for cilta-cel manufacturing between 3/1/2022-12/31/2022 at 16 US academic medical centers were included. RESULTS: 255 patients underwent leukapheresis and 236 (92.5%) received cilta-cel. Of leukapheresed patients, 56% would not have met CARTITUDE-1 trial eligibility criteria. Manufacturing failure rates at first attempt and overall were 6% and 1%, respectively. Median prior lines of therapy were 6. In treated patients (N=236), cytokine release syndrome was seen in 75% (>= grade 3: 5%), immune effector cell-associated neurotoxicity syndrome in 14% (>= grade 3: 4%), and delayed neurotoxicity in 10%. Best overall and >= CR rates were as follows: infused patients (N=236): 89% and 70%; patients receiving conforming CAR-T product (N=191) 94% and 74%; conforming CAR-T product with fludarabine/cyclophosphamide lymphodepletion (N=152): 95% and 76%, respectively. Non-relapse mortality was 10%, most commonly from infection. After median follow-up of 13 months from CAR-T, median progression-free survival (PFS) was not reached, with 12- month estimate being 68% (95% CI: 62-74%). High ferritin levels, high-risk cytogenetics, and extramedullary disease were independently associated with inferior PFS, with a signal for prior BCMA-TT (p=0.08). Second primary malignancies (SPMs) excluding non-melanoma skin cancers were seen in 5.5% and myeloid malignancies/acute leukemia in 1.7%. We observed a favorable efficacy profile of standard of care cilta-cel in RRMM despite more than half the patients not meeting CARTITUDE-1 eligibility criteria.

  View details for DOI 10.1182/blood.2024025945

  View details for PubMedID 39365257

• Best Practice Considerations by The American Society of Transplant and Cellular Therapy: Infection Prevention and Management after Chimeric Antigen Receptor T Cell Therapy for Hematological Malignancies. Transplantation and cellular therapy Shahid, Z., Jain, T., Dioverti, V., Pennisi, M., Mikkilineni, L., Kambhampati, S., Shah, N. N., Dadwal, S., Papanicolaou, G., Hamadani, M., Carpenter, P. A., Alfaro, G. M., Seo, S. K., Hill, J. A. 2024

  Abstract

  Chimeric antigen receptor (CAR) T-cell therapy is rapidly advancing, offering promising treatments for patients with hematological malignancy. However, associated infectious complications remain a significant concern because of their contribution to patient morbidity and non-relapse mortality. Recent epidemiological insights shed light on risk factors for infections after CAR T-cell therapy. However, the available evidence is predominantly retrospective, highlighting a need for further prospective studies. Institutions are challenged with managing infections after CAR T-cell therapy but variations in the approaches taken underscore the importance of standardizing infection prevention and management protocols across different healthcare settings. Therefore, the Infectious Diseases Special Interest Group of the American Society of Transplantation and Cellular Therapy assembled an expert panel to develop best practice considerations. The aim was to guide healthcare professionals in optimizing infection prevention and management for CAR T-cell therapy recipients and advocates for early consultation of Infectious Diseases during treatment planning phases given the complexities involved. By synthesizing current evidence and expert opinion these best practice considerations provide the basis for understanding infection risk after CAR T-cell therapies and propose risk-mitigating strategies in children, adolescents, and adults. Continued research and collaboration will be essential to refining and effectively implementing these recommendations.

  View details for DOI 10.1016/j.jtct.2024.07.018

  View details for PubMedID 39084261

• Integrating Immune Therapies for the Treatment of Multiple Myeloma. Journal of the National Comprehensive Cancer Network : JNCCN Mikkilineni, L., Sidana, S. 2023; 21 (12): 1303-1311

  Abstract

  Patients with relapsed or refractory multiple myeloma (RRMM) that is refractory to a proteasome inhibitor, an immunomodulatory drug (IMiD), and an anti-CD38 antibody (triple-class refractory MM) have poor outcomes. Recently, 2 classes of T-cell engaging therapies-CAR T-cell therapy and bispecific T-cell engaging antibodies (BsAbs)-have resulted in unprecedented response rates and survival outcomes in these heavily pretreated patients. The most common targets are BCMA and GPRC5D, with other targets in development. The main classes of adverse effects include cytokine release syndrome, neurotoxicity, infections, and cytopenias, as well as adverse effects unique to specific products. As of September 2023, 2 BCMA-targeting CAR-T cell products, 2 BCMA-targeting BsAbs, and 1 GPRC5D-targeting BsAb, are FDA-approved for standard-of-care use in patients with RRMM who received at least 4 prior lines of therapy, including prior treatment with a proteasome inhibitor, an IMiD, and an anti-CD38 antibody. Earlier-line use is under investigation and has shown promising results. Several other investigational CAR-T constructs and bispecific antibodies are in clinical development. As these therapies become more widely used, including in earlier-line setting, efforts to understand optimal sequencing and mitigate toxicities remain critical.

  View details for DOI 10.6004/jnccn.2023.7100

  View details for PubMedID 38081142

• Early and Late Toxicities of Chimeric Antigen Receptor T-Cells. Hematology/oncology clinics of North America Epperly, R., Giordani, V. M., Mikkilineni, L., Shah, N. N. 2023

  Abstract

  As chimeric antigen receptor (CAR) T-cell therapy is increasingly integrated into clinical practice across a range of malignancies, identifying and treating inflammatory toxicities will be vital to success. Early experiences with CD19-targeted CAR T-cell therapy identified cytokine release syndrome and neurotoxicity as key acute toxicities and led to unified initiatives to mitigate the influence of these complications. In this section, we provide an update on the current state of CAR T-cell-related toxicities, with an emphasis on emerging acute toxicities affecting additional organ systems and considerations for delayed toxicities and late effects.

  View details for DOI 10.1016/j.hoc.2023.05.010

  View details for PubMedID 37349152

• The impact of race, ethnicity, and obesity on CAR T-cell therapy outcomes. Blood advances Faruqi, A. J., Ligon, J. A., Borgman, P., Steinberg, S. M., Foley, T., Little, L., Mackall, C. L., Lee, D. W., Fry, T. J., Shalabi, H., Brudno, J., Yates, B., Mikkilineni, L., Kochenderfer, J., Shah, N. N. 2022; 6 (23): 6040-6050

  Abstract

  Cancer outcomes with chemotherapy are inferior in patients of minority racial/ethnic groups and those with obesity. Chimeric antigen receptor (CAR) T-cell therapy has transformed outcomes for relapsed/refractory hematologic malignancies, but whether its benefits extend commensurately to racial/ethnic minorities and patients with obesity is poorly understood. With a primary focus on patients with B-cell acute lymphoblastic leukemia (B-ALL), we retrospectively evaluated the impact of demographics and obesity on CAR T-cell therapy outcomes in adult and pediatric patients with hematologic malignancies treated with CAR T-cell therapy across 5 phase 1 clinical trials at the National Cancer Institute from 2012 to 2021. Among 139 B-ALL CAR T-cell infusions, 28.8% of patients were Hispanic, 3.6% were Black, and 29.5% were overweight/obese. No significant associations were found between race, ethnicity, or body mass index (BMI) and complete remission rates, neurotoxicity, or overall survival. Hispanic patients were more likely to experience severe cytokine release syndrome compared with White non-Hispanic patients even after adjusting for leukemia disease burden and age (odds ratio, 4.5; P = .001). A descriptive analysis of patients with multiple myeloma (n = 24) and non-Hodgkin lymphoma (n = 23) displayed a similar pattern to the B-ALL cohort. Our findings suggest CAR T-cell therapy may provide substantial benefit across a range of demographics characteristics, including for those populations who are at higher risk for chemotherapy resistance and relapse. However, toxicity profiles may vary. Therefore, efforts to improve access to CAR therapy for underrepresented populations and elucidate mechanisms of differential toxicity among demographic groups should be prioritized.

  View details for DOI 10.1182/bloodadvances.2022007676

  View details for PubMedID 35939781

• Infectious Complications of CAR T-Cell Therapy Across Novel Antigen Targets in the first 30 days. Blood advances Mikkilineni, L., Yates, B., Steinberg, S. M., Shahani, S. A., Molina, J. C., Palmore, T. N., Lee, D. W., Kaplan, R. N., Mackall, C. L., Fry, T. J., Gea-Banacloche, J., Jerussi, T. D., Nussenblatt, V., Kochenderfer, J. N., Shah, N. N. 2021

  Abstract

  Infections are a known complication of chimeric antigen receptor (CAR) T-cell therapy with data largely emerging from CD19 CAR T-cell targeting. As CAR T-cell therapy continues to evolve, infection risks and management thereof will become increasingly important to optimize outcomes across the spectrum of antigens and disease targeted. We retrospectively characterized infectious complications occurring in 162 children and adults treated amongst five phase 1 CAR T-cell clinical trials. Trials included targeting of CD19, CD22, disialoganglioside (GD2) or B-cell maturation antigen (BCMA). Fifty-three patients (32.7%) had 76 infections between lymphocyte depleting (LD) chemotherapy and day 30; with the majority (80.5%) occurring between day 0 (D0) and day 30 (D30). By trial, the highest proportion of infections was seen with CD22 CAR T-cells (n=23/53; 43.4%), followed by BCMA CAR T-cells(n=9/24; 37.5%). By disease, patients with multiple myeloma, had the highest proportion of infections (9 of 24, 37.5%) followed by acute lymphoblastic leukemia (36 of 102, 35.3%). Grade 4 infections were rare (n=4, 2.5%). Between D0 and D30, bacteremia and bacterial site infections were the most common infection type. In univariate analysis, increasing prior lines of therapy, recent infection within 100 days of LD chemotherapy, corticosteroid or tocilizumab use and fever and neutropenia (F&N) were associated with a higher risk of infection. In a multivariable analysis, only prior lines of therapy and recent infection were associated with higher risk of infection. In conclusion, we provide a broad overview of infection risk within the first 30 days post infusion across a host of multiple targets and diseases, elucidating both unique characteristics and commonalities highlighting aspects important to improving patient outcomes.

  View details for DOI 10.1182/bloodadvances.2021004896

  View details for PubMedID 34619768

• Infectious Complications Associated with CAR T-Cell Therapy Mikkilineni, L., Shahani, S., Yates, B., Steinberg, S. M., Palmore, T., Nussenblatt, V., Lee, D. W., Kaplan, R. N., Mackall, C. L., Fry, T. J., Gea-Banacloche, J., Jerussi, T., Kochenderfer, J. N., Shah, N. N. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-131170

  View details for Web of Science ID 000577164603181