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Serbian Association for Cancer Research SDIRSACR

different mechanisms of action and non-overlapping toxicities simultaneously, the chance of resistant clones surviving
was reduced, and responses were improved.
A landmark example of this approach was the MOPP regimen (mechlorethamine, vincristine, procarbazine, prednisone),
which dramatically improved outcomes in Hodgkin lymphoma (HL) and became the first chemotherapy combination
to cure a human cancer. Subsequently, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) emerged
as the standard treatment for aggressive non-Hodgkin lymphomas (NHL), while in acute myeloid leukemia (AML),
the combination of cytarabine and an anthracycline (the “7+3” regimen) set the standard induction therapy. These
regimens became the backbone of treatment for decades, laying the groundwork for integrating newer agents.
The advent of targeted therapies and immunotherapy
The therapeutic revolution accelerated in the 1990s and 2000s with the emergence of targeted therapies and
immunotherapies. The introduction of rituximab in 1997, an anti-CD20 monoclonal antibody, was pivotal, transforming
treatment for B-cell NHL and leading to widespread incorporation of antibody-based therapy in frontline regimens
such as R-CHOP. Rituximab’s success proved the concept that harnessing the immune system to target specific antigens
could augment or replace chemotherapy.
Molecular targeted therapy took a giant leap forward with the development of imatinib in 2001, which specifically
inhibits the BCR-ABL fusion kinase that drives chronic myeloid leukemia (CML). Imatinib turned CML into a chronic,
manageable disease and demonstrated the feasibility of precision medicine, targeting the cancer’s genetic drivers.
Since then, numerous targeted agents have been developed for specific genetic and epigenetic abnormalities in
hematological malignancies, including FLT3 and IDH inhibitors for AML, BTK inhibitors for mantle cell lymphoma (MCL)
and chronic lymphocytic leukemia (CLL).
Integration of novel agents into combination regimens
The current standard of care for many hematological malignancies involves combinations of cytotoxic chemotherapy
with targeted agents and immunotherapies to maximize efficacy and overcome resistance. In AML, for example, the
integration of FLT3 inhibitors with induction chemotherapy improves survival for patients harboring FLT3 mutations.
Similarly, the combination of the BCL-2 inhibitor venetoclax with hypomethylating agents (azacytidine and decitabine)
provides a chemotherapy-free induction regimen for older or unfit patients, achieving high complete remission (CR)
rates with a more tolerable safety profile.
In multiple myeloma (MM), treatment has shifted away from conventional chemotherapy toward combinations of
proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies. Regimens such as the quadruplet
therapy of daratumumab, bortezomib, lenalidomide, and dexamethasone (D-VRd) have become standard in the
frontline setting, particularly for transplant-eligible patients. In this population, autologous stem cell transplantation
(ASCT) remains an integral component of initial therapy, typically following induction and followed by consolidation
and maintenance strategies. These regimens have demonstrated significantly improved progression-free survival (PFS)
and overall survival (OS) compared to older chemotherapy-based approaches, with reduced toxicity. Their success is
due not only to potent anti-myeloma effects but also to their ability to enhance immune-mediated tumor clearance
and achieve high rates of minimal residual disease (MRD) negativity, supporting durable disease control and improved
quality of life.
In lymphomas such as HL, novel agents including the antibody-drug conjugate brentuximab vedotin and immune
checkpoint inhibitors targeting PD-1 (nivolumab and pembrolizumab) have increased the depth and durability of
remission. Notably, these agents have reduced the reliance on salvage regimens followed by ASCT as consolidation for
relapsed disease, sparing patients from the morbidity and late effects of high-dose chemotherapy and transplantation.
In MCL, incorporation of the BTK inhibitors among other novel agents has improved outcomes in relapsed/refractory
settings and increasingly as part of frontline regimens, reducing the necessity for intensive therapies including ASCT
in many patients. The less toxic nature of these novel agents allows older or less fit patients to achieve long-lasting
remissions.
The significance of complete remission and minimal residual disease
Achieving CR with initial therapy is strongly associated with improved long-term outcomes across hematological
malignancies. CR is defined not only by the absence of detectable disease on conventional imaging and bone marrow
evaluation but increasingly by molecular assessments of MRD. MRD negativity has emerged as a powerful prognostic
marker, correlating with longer DFS and OS in leukemia, lymphoma, and myeloma. Early achievement of deep remission
can reduce the need for subsequent intensive therapies such as SCT and decrease the risk of relapse.
Harnessing the tumor microenvironment, chemotherapy-free regimens and improved tolerability
A pivotal advancement underlying many novel therapies is a better understanding of the tumor microenvironment
(TME), the surrounding immune cells, stromal cells, blood vessels, and extracellular matrix that interact with and support
malignant cells. The TME plays a critical role in promoting tumor growth, mediating immune evasion, and fostering
resistance to therapy. Therapeutics like IMiDs and monoclonal antibodies disrupt these supportive interactions and
activate immune effector cells. Similarly, checkpoint inhibitors restore exhausted T cells in the TME, reversing tumor-

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