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SDIRSACR Oncology Insights

high-intensity pulses capable of delivering FLASH-relevant dose rates per pulse at clinically relevant energies. Very
High Energy Electron (VHEE) beams generated by laser-driven accelerators further extend this paradigm. VHEEs—in
the range of 100–250 MeV—combine deep penetration with precise focusing, potentially enabling conformal dose
distributions even in deep-seated tumors. Laser-driven proton beams represent another frontier. Proton therapy’s
hallmark Bragg peak enables maximal tumor dose deposition with sharp distal fall-off, but conventional cyclotrons and
synchrotrons are large and costly. Laser-plasma acceleration may yield compact, cost-effective proton sources capable
of UHDR delivery, marrying the spatial selectivity of protons with FLASH sparing.

4. Clinical Integration and Future Directions
Realizing the promise of these novel modalities demands rigorous translational pathways encompassing dosimetric
validation, preclinical mechanistic studies, and carefully designed clinical trials. Technological hurdles—such as beam
stability, real-time dosimetry at UHDRs, and synchronization with immunotherapeutic dosing—must be addressed.
Concurrently, the development of robust biomarkers for normal tissue response and immune activation will guide
patient selection and adaptive treatment strategies. Furthermore, computational modeling and artificial intelligence
will play pivotal roles in optimizing multi modality schedules, predicting toxicity, and personalizing combination
regimens.
In conclusion, the integration of chemotherapy synergistic approaches, hypofractionated high-dose radiation with
immunotherapy, and laser-based particle acceleration technologies heralds a new era in radiation oncology. By
capitalizing on both physical and biological synergies, these strategies strive to overcome the current therapeutic
plateau—offering potent tumor control, diminished radiation damage, and improved patient outcomes.

Acknowledgments and funding: The ELI ALPS project (GINOP-2.3.6-15-2015-00001) is supported by the European
Union and co-financed by the European Regional Development Fund.

L03
Benefits of combination therapies in the treatment of hematological malignancies

Zorica Cvetković 1,2

1 Department of Hematology, Clinic for Internal medicine, University Hospital Medical CenterZemun, Belgrade, Serbia
2 Medical Faculty, University of Belgrade, Belgrade, Serbia

Keywords: hematological malignancies, combination therapy, targeted therapy, benefits

Hematological malignancies, including acute leukemias, and mature lymphoid and myeloid neoplasms, are inherently
systemic, involving the bone marrow, blood, and lymphatic tissues from disease onset. Unlike solid tumors, they are not
amenable to curative local therapies. Surgery is typically limited to diagnostic procedures or emergency management
of complications (e.g., organ rupture, spinal cord compression). At the same time, radiotherapy is reserved for
specific indications, including central nervous system (CNS) involvement in high-risk acute leukemia (AL) or aggressive
lymphomas, as well as early-stage indolent lymphomas, though it remains adjunctive. Consequently, treatment
relies almost exclusively on systemic therapies. The management of hematological malignancies represents one of
the most rapidly evolving fields in medical oncology. These cancers arise in blood-forming and lymphoid tissues and
involve immune system cells, making them particularly responsive to therapies with cytotoxic and immunomodulatory
mechanisms. Over the past century, treatment has progressed from single-agent chemotherapy to rationally designed
combination regimens that incorporate chemotherapy, targeted therapies, and immunotherapies, including bispecific
antibodies and CAR T-cell therapy, as well as epigenetic modulators. This multifaceted approach has significantly
improved response depth and durability, extended survival, and enhanced quality of life, while reducing treatment-
related toxicity and long-term morbidity.
Historical perspective and the emergence of combination chemotherapy in hematological malignancies
The origins of chemotherapy lie in observations during the early World War II period, that exposure to mustard gas
caused profound lymphoid suppression. This insight was translated into the first clinical use of alkylating agents to
treat lymphoma, specifically with the drug mechlorethamine in 1942. The initial successes of these cytotoxic agents,
which damage DNA to kill rapidly dividing cells, were limited by the rapid emergence of resistant cancer clones. This
limitation spurred the development of combination chemotherapy in the 1950s and 1960s. By using agents with

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