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Haematological malignancies, including leukemia, lymphoma, and multiple myeloma, present significant treatment challenges due to the emergence of drug resistance. This research explores innovative therapeutic strategies and emerging molecular targets aimed at overcoming drug resistance in these cancers. We highlight targeted therapies, immunotherapy, epigenetic modulators, and novel drug delivery systems as promising approaches in addressing resistance mechanisms.
Keywords
Haematological Cancers, Drug Resistance, Targeted Therapy, Immunotherapy
Introduction
Haematological cancers, including leukemia, lymphoma, and multiple myeloma, account for a substantial proportion of oncological diseases. While significant advancements have been made in chemotherapy, immunotherapy, and targeted treatments, the development of drug resistance remains a major barrier to long-term remission and patient survival. Resistance to chemotherapeutic agents arises through a variety of mechanisms. Genetic mutations can alter drug targets, rendering treatments ineffective. Changes in drug transport, such as increased efflux via ATP-binding cassette (ABC) transporters or reduced drug uptake, can limit intracellular drug accumulation. Additionally, activation of alternative signaling pathways allows cancer cells to bypass the intended effects of therapy, sustaining proliferation and survival. The tumor microenvironment (TME) also plays a crucial role, providing protective niches that shield malignant cells from cytotoxic agents through cell–cell interactions, cytokine secretion, and metabolic adaptations. To improve patient outcomes, it is essential to identify and target these resistance mechanisms. Novel therapeutic strategies, including next-generation small-molecule inhibitors, monoclonal antibodies, epigenetic modulators, and immunotherapies such as CAR-T cells, hold promise in overcoming resistance. A deeper understanding of the molecular and cellular factors driving drug resistance will enable the development of more effective, personalized treatment approaches for haematological malignancies.
Fig.1 Hematological cancers
Mechanisms of Drug Resistance in Haematological Cancers
1. Genetic and Epigenetic Alterations
Genomic instability in haematological malignancies frequently leads to mutations in key oncogenes and tumor suppressors, which drive both disease progression and drug resistance. For example:
BCR-ABL mutations in chronic myeloid leukemia (CML): Point mutations in the ABL kinase domain, such as the T315I mutation, confer resistance to tyrosine kinase inhibitors (TKIs) like imatinib.
TP53 mutations in leukemia and lymphoma: Loss of TP53 function results in defective apoptosis, reducing the effectiveness of DNA-damaging agents such as alkylating agents and anthracyclines.
Epigenetic modifications: DNA methylation and histone modifications can silence tumor suppressor genes or upregulate resistance-associated genes. For example, hypermethylation of the CDKN2A gene leads to loss of p16INK4a, promoting unchecked cell cycle progression. Epigenetic modulators, such as DNA methyltransferase inhibitors (e.g., azacitidine) and histone deacetylase inhibitors (e.g., vorinostat), are being explored to reverse these resistance mechanisms.
2. Efflux Pump Overexpression
Cancer cells can actively expel chemotherapeutic agents, reducing intracellular drug accumulation and efficacy.
P-glycoprotein (P-gp, ABCB1): Overexpression of this ATP-binding cassette (ABC) transporter is a well-known mechanism of multidrug resistance (MDR), leading to decreased intracellular concentrations of agents such as anthracyclines, vinca alkaloids, and TKIs.
Other ABC transporters: ABCC1 (MRP1) and ABCG2 (BCRP) also contribute to drug resistance in acute myeloid leukemia (AML) and multiple myeloma.
Therapeutic strategies: Inhibitors of efflux pumps, such as verapamil and tariquidar, have been explored but with limited clinical success due to toxicity and compensatory resistance mechanisms.
3. Activation of Compensatory Pathways
When primary signaling pathways are inhibited by targeted therapies, cancer cells can activate alternative survival mechanisms:
PI3K/AKT/mTOR pathway: Frequently upregulated in lymphomas and leukemias, this pathway promotes cell survival and proliferation. Resistance to PI3K inhibitors (e.g., idelalisib) often arises through compensatory AKT activation.
JAK/STAT pathway: Hyperactivation of this pathway, particularly in myeloproliferative neoplasms (MPNs) and certain lymphomas, sustains proliferation and immune evasion. Mutations in JAK2 (e.g., JAK2 V617F) contribute to resistance against JAK inhibitors like ruxolitinib.
RAS/MAPK pathway: Aberrant activation of RAS signaling can counteract BRAF or MEK inhibitors, leading to therapeutic resistance in some hematologic cancers.
Therapeutic strategies: Combination therapies targeting multiple pathways, such as dual PI3K and mTOR inhibitors, are under investigation to prevent compensatory activation.
4. Tumor Microenvironment (TME) Interactions
The bone marrow niche and lymphoid microenvironments provide a sanctuary for malignant cells, enabling resistance through:
Stromal cell support: Bone marrow stromal cells (BMSCs) secrete cytokines like IL-6, IL-8, and CXCL12, enhancing cancer cell survival in multiple myeloma and chronic lymphocytic leukemia (CLL).
Adhesion-mediated resistance: Interactions between malignant cells and stromal components via integrins (e.g., VLA-4) and cadherins protect against apoptosis induced by chemotherapy.
Hypoxia-induced resistance: The hypoxic bone marrow microenvironment promotes stem-like properties and upregulates hypoxia-inducible factors (HIFs), reducing sensitivity to chemotherapy and radiotherapy.
Immunosuppressive milieu: The TME recruits regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and macrophages (TAMs) that secrete TGF-β and IL-10, blunting the effectiveness of immunotherapy.
Therapeutic strategies: Disrupting stromal interactions with CXCR4 inhibitors (e.g., plerixafor) or targeting immune evasion mechanisms with checkpoint inhibitors (e.g., pembrolizumab) is being explored to overcome TME-mediated resistance.
Fig 1. Mechanisms of Drug Resistance in Haematological Cancers
Emerging Therapeutic Approaches in Haematological Cancers
As resistance to conventional chemotherapies continues to challenge treatment success, innovative therapeutic strategies are being developed to enhance efficacy and overcome resistance mechanisms. These approaches include targeted therapies, immunotherapy, epigenetic modulation, and novel drug delivery systems.
1. Targeted Therapies
Targeted therapies aim to selectively inhibit oncogenic drivers and survival pathways critical to haematological malignancies while minimizing toxicity to normal cells.
Tyrosine Kinase Inhibitors (TKIs)
TKIs block aberrant kinase activity that drives uncontrolled proliferation in leukemias:
Next-generation TKIs (e.g., ponatinib, asciminib): Designed to overcome resistance mutations in chronic myeloid leukemia (CML), such as the T315I mutation in BCR-ABL, which confers resistance to first- and second-generation TKIs (imatinib, dasatinib, nilotinib).
FLT3 inhibitors (e.g., gilteritinib, quizartinib): Target FLT3-ITD mutations in acute myeloid leukemia (AML), a key driver of disease progression and relapse.
BCL-2 Inhibitors
The BCL-2 family of proteins regulates apoptosis, and overexpression of BCL-2 allows cancer cells to evade programmed cell death.
Venetoclax: A potent BCL-2 inhibitor that induces apoptosis in chronic lymphocytic leukemia (CLL) and AML, particularly effective in combination therapies with hypomethylating agents (e.g., azacitidine, decitabine).
Proteasome Inhibitors
Proteasome inhibition disrupts protein degradation pathways, leading to apoptotic cell death in malignant cells.
Carfilzomib and ixazomib: More selective proteasome inhibitors used in multiple myeloma (MM), offering improved efficacy and reduced toxicity compared to bortezomib.
2. Immunotherapy
Immunotherapy leverages the immune system to selectively eliminate cancer cells, representing a paradigm shift in haematological cancer treatment.
Chimeric Antigen Receptor (CAR) T-Cell Therapy
CAR-T cell therapy genetically engineers T-cells to express chimeric receptors that recognize and destroy malignant cells:
CD19-targeted CAR-T cells (e.g., tisagenlecleucel, axicabtagene ciloleucel): Highly effective in B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL).
Next-generation CAR-T therapies: Research is expanding to other targets, such as BCMA (B-cell maturation antigen) for multiple myeloma and CD22/CD20 for relapsed/refractory B-cell malignancies.
Immune Checkpoint Inhibitors
Checkpoint proteins like PD-1/PD-L1 suppress T-cell activity, allowing tumors to evade immune attack.
PD-1 inhibitors (pembrolizumab, nivolumab): Restore T-cell function in Hodgkin’s lymphoma and T-cell lymphomas, particularly effective in patients with high PD-L1 expression.
Bispecific Antibodies
Bispecific T-cell engagers (BiTEs) facilitate direct interaction between T-cells and tumor cells, promoting immune-mediated cytotoxicity.
Blinatumomab: A CD19/CD3 bispecific antibody that bridges T-cells and B-cell leukemia cells, leading to enhanced tumor lysis.
3. Epigenetic Modulation
Epigenetic dysregulation contributes to treatment resistance and disease progression in haematological cancers. Targeting these reversible modifications has shown promising results.
Histone Deacetylase (HDAC) Inhibitors
HDACs regulate chromatin structure and gene expression. Inhibition of HDACs can restore tumor suppressor gene function and induce apoptosis.
Panobinostat and vorinostat: Approved for multiple myeloma and T-cell lymphomas, often used in combination with other therapies.
DNA Methyltransferase (DNMT) Inhibitors
Aberrant DNA methylation silences tumor suppressor genes, contributing to malignancy.
Azacitidine and decitabine: Hypomethylating agents that reactivate silenced genes in AML and myelodysplastic syndromes (MDS), improving responses to chemotherapy and targeted agents.
4. Novel Drug Delivery Systems
Innovative drug delivery strategies improve therapeutic precision, reduce systemic toxicity, and enhance drug stability.
Nanoparticle-Based Delivery
Nanotechnology enables selective drug targeting to tumor cells while sparing normal tissues.
Liposomal doxorubicin (e.g., Doxil): Improves drug accumulation in tumors and reduces cardiotoxicity compared to free doxorubicin in lymphoma and multiple myeloma.
Lipid nanoparticle (LNP) delivery systems: Enhance the stability and delivery of RNA-based therapies and small-molecule inhibitors.
Conjugated Antibody-Drug Complexes (ADCs)
Antibody-drug conjugates combine a monoclonal antibody with a cytotoxic agent, allowing targeted drug delivery with minimal off-target effects.
Brentuximab vedotin: A CD30-directed ADC for Hodgkin’s lymphoma and anaplastic large cell lymphoma (ALCL).
Polatuzumab vedotin: Targets CD79b in B-cell lymphomas, delivering potent cytotoxic payloads specifically to malignant cells.
Case Studies on Emerging Therapeutic Approaches in Haematological Cancers
Study/Trial
Cancer Type
Therapeutic Approach
Key Findings
Reference
Pivotal PACE Trial (Ponatinib)
Chronic Myeloid Leukemia (CML)
Next-generation TKI (Ponatinib)
Overcame T315I mutation resistance, with 54% major cytogenetic response (MCyR) in resistant CML patients
Improved 3-year PFS (83% vs. 76%) compared to ABVD
Connors et al., 2018
ALPINE Trial (Zanubrutinib vs. Ibrutinib in Relapsed CLL)
Chronic Lymphocytic Leukemia (CLL)
Next-gen BTK inhibitor (Zanubrutinib)
Better PFS and fewer cardiac toxicities vs. Ibrutinib
Hillmen et al., 2022
Polatuzumab Vedotin + Bendamustine + Rituximab
Relapsed/Refractory DLBCL
ADC (Polatuzumab Vedotin)
Increased CR rate (40% vs. 15%) compared to standard therapy
Tilly et al., 2020
RESULTS AND DISCUSSION
1. Results
The clinical trials and case studies analyzed demonstrate the efficacy of emerging therapies in overcoming resistance and improving patient outcomes in haematological cancers. Below are key findings:
1.1 Targeted Therapies Improve Response Rates and Overcome Resistance
Next-generation tyrosine kinase inhibitors (TKIs) such as ponatinib have shown significant efficacy in overcoming resistance mutations (e.g., T315I in CML). In the PACE trial, ponatinib achieved a 54% major cytogenetic response (MCyR) in patients resistant to prior TKIs.
BCL-2 inhibitors, particularly venetoclax, have been highly effective in CLL and AML. The MURANO trial demonstrated an 85% progression-free survival (PFS) at 3 years with venetoclax-rituximab, significantly outperforming chemoimmunotherapy.
1.2 Immunotherapy Provides Durable Responses in Refractory Disease
CAR-T cell therapy has revolutionized treatment for relapsed/refractory (R/R) B-cell malignancies. The ZUMA-1 trial showed an 82% objective response rate (ORR) and 54% complete remission (CR) in refractory DLBCL patients receiving axicabtagene ciloleucel (CD19 CAR-T).
Immune checkpoint inhibitors (ICIs), such as nivolumab, have demonstrated durable responses in Hodgkin’s lymphoma, with the CheckMate 205 trial reporting a 69% ORR in relapsed/refractory cases.
Brentuximab vedotin (BV) has significantly improved outcomes in Hodgkin’s lymphoma. The ECHELON-1 trial showed that BV combined with AVD chemotherapy improved 3-year PFS (83% vs. 76%) compared to standard ABVD.
Polatuzumab vedotin, an anti-CD79b ADC, increased complete remission rates from 15% to 40% in relapsed/refractory DLBCL when combined with bendamustine and rituximab.
1.4 Epigenetic Modulation and Novel Drug Delivery Systems Show Promise
Histone deacetylase (HDAC) inhibitors (e.g., panobinostat, vorinostat) and DNA methyltransferase inhibitors (e.g., azacitidine, decitabine) have shown efficacy in AML and myelodysplastic syndromes, particularly in combination therapies.
Nanoparticle-based drug delivery (e.g., liposomal doxorubicin) enhances drug bioavailability while reducing toxicity, improving therapeutic outcomes in lymphomas and multiple myeloma.
2. Discussion
2.1 Addressing Drug Resistance Through Combination Therapies
Many haematological malignancies develop resistance through genetic mutations, compensatory pathway activation, and tumor microenvironment interactions. Emerging therapies effectively counteract these mechanisms:
TKI resistance in CML (e.g., BCR-ABL mutations) has been addressed by next-generation inhibitors like ponatinib and asciminib. However, new mutations may still emerge, necessitating continued development of more potent inhibitors.
BCL-2 inhibitor resistance in CLL and AML can develop via MCL-1 upregulation. Combination strategies with MCL-1 inhibitors or BH3 mimetics are under investigation.
2.2 Challenges and Limitations of Immunotherapy
While immunotherapy has produced durable responses, several challenges remain:
CAR-T therapy limitations: High response rates in B-cell malignancies are countered by significant toxicities such as cytokine release syndrome (CRS) and neurotoxicity. Strategies like IL-6 blockade (tocilizumab) and next-generation CAR designs (e.g., dual-targeting CARs) aim to mitigate these issues.
Checkpoint inhibitor resistance: Some haematological cancers, such as AML, exhibit low PD-L1 expression, reducing the efficacy of PD-1/PD-L1 inhibitors. Combination approaches with hypomethylating agents or chemotherapy are being explored.
2.3 The Role of Personalized and Precision Medicine
Genomic profiling is becoming increasingly important in treatment selection. Identifying resistance mutations (e.g., FLT3, JAK2, TP53) allows for tailored therapies, improving patient outcomes.
Minimal residual disease (MRD) monitoring using next-generation sequencing (NGS) and flow cytometry enables early detection of relapse, guiding treatment adjustments.
2.4 Future Directions in Drug Delivery and Novel Therapies
Bispecific antibodies (e.g., blinatumomab) and trispecific antibodies are expanding immunotherapeutic options, particularly in aggressive lymphomas and leukemias.
Antibody-drug conjugates (ADCs) are being improved with more stable linkers and potent cytotoxic payloads, increasing their efficacy while minimizing off-target toxicity.
Nanoparticle-based therapy and RNA-based approaches (e.g., siRNA or mRNA vaccines) are being investigated to enhance precision targeting of malignant cells.
CONCLUSION
Emerging therapeutic approaches have significantly improved outcomes in haematological cancers, particularly for patients with relapsed or refractory disease. However, drug resistance, immunotherapy-related toxicities, and heterogeneity in patient responses remain key challenges. Future research should focus on:
Optimizing combination therapies to prevent resistance.
Enhancing the safety and efficacy of immunotherapy through better toxicity management and novel CAR-T designs.
Advancing precision medicine through genomic profiling, MRD monitoring, and personalized treatment strategies.
Developing next-generation drug delivery systems to improve efficacy while reducing toxicity.
By addressing these challenges, the field of haematological oncology can continue to evolve toward more effective, durable, and personalized treatment strategies.
REFERENCES
Cortes, J. E., et al. (2013). "Ponatinib in refractory chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia." New England Journal of Medicine, 369(19), 1783-1796.
Hochhaus, A., et al. (2017). "Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: Results from the BFORE trial." Journal of Clinical Oncology, 36(3), 231-237.
Perl, A. E., et al. (2019). "Gilteritinib or chemotherapy for relapsed FLT3-mutated AML." New England Journal of Medicine, 381(18), 1728-1740.
Seymore, J. F., et al. (2018). "Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia." New England Journal of Medicine, 378(12), 1107-1120.
Moreau, P., et al. (2019). "Venetoclax in relapsed multiple myeloma: BELLINI trial results." Lancet Oncology, 20(12), 1630-1642.
Maude, S. L., et al. (2018). "Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia." New England Journal of Medicine, 378(5), 439-448.
Locke, F. L., et al. (2017). "Phase 1 results of ZUMA-1: Axicabtagene ciloleucel (KTE-C19) for refractory large B-cell lymphoma." Lancet Oncology, 18(1), 44-53.
Schuster, S. J., et al. (2019). "Tisagenlecleucel in adult relapsed/refractory diffuse large B-cell lymphoma." New England Journal of Medicine, 380(1), 45-56.
Ansell, S. M., et al. (2019). "CheckMate 205: Nivolumab for relapsed Hodgkin lymphoma." Journal of Clinical Oncology, 37(15), 1283-1294.
Lesokhin, A. M., et al. (2016). "PD-1 blockade in multiple myeloma: Early results from a phase I trial." Blood, 128(13), 1824-1833.
Viardot, A., et al. (2016). "Blinatumomab for minimal residual disease in acute lymphoblastic leukemia." New England Journal of Medicine, 374(6), 523-532.
Topp, M. S., et al. (2011). "Blinatumomab as a targeted therapy for relapsed B-cell acute lymphoblastic leukemia." Blood, 118(20), 5434-5441.
Connors, J. M., et al. (2018). "Brentuximab vedotin plus chemotherapy for stage III or IV Hodgkin’s lymphoma." New England Journal of Medicine, 378(4), 331-344.
Tilly, H., et al. (2020). "Polatuzumab vedotin with bendamustine and rituximab in relapsed/refractory DLBCL." Journal of Clinical Oncology, 38(2), 155-165.
Sehn, L. H., et al. (2021). "Mosunetuzumab in relapsed/refractory B-cell lymphomas: A bispecific antibody approach." Blood, 138(7), 544-556.
Fenaux, P., et al. (2009). "Azacitidine prolongs survival in higher-risk myelodysplastic syndromes." Lancet Oncology, 10(3), 223-232.
Dombret, H., et al. (2015). "Phase III trial of azacitidine in elderly AML patients." Blood, 126(3), 291-299.
Garcia-Manero, G., et al. (2018). "Decitabine-based epigenetic therapy in myelodysplastic syndromes." Blood Advances, 2(10), 1135-1142.
San-Miguel, J. F., et al. (2013). "Panobinostat for relapsed multiple myeloma: Phase III PANORAMA-1 trial." Lancet Oncology, 14(6), 119-128.
Kirschbaum, M., et al. (2014). "Vorinostat in combination with chemotherapy for relapsed AML." Leukemia Research, 38(12), 1335-1340.
Gabizon, A., et al. (1994). "Liposome-encapsulated doxorubicin: Pharmacokinetics and clinical implications." Cancer Research, 54(4), 987-992.
Barenholz, Y. (2012). "Doxil®—The first FDA-approved nano-drug: Lessons learned." Journal of Controlled Release, 160(2), 117-134.
Sawant, R., & Torchilin, V. (2012). "Challenges in development of targeted liposomal therapeutics." Frontiers in Pharmacology, 3, 141.
Kranz, L. M., et al. (2016). "RNA-based immunotherapy targeting mutated KRAS in AML." Nature Medicine, 22(6), 704-712.
Sahin, U., et al. (2017). "mRNA vaccines for personalized cancer immunotherapy." Nature, 547(7662), 222-226.
Burger, J. A., et al. (2020). "Targeting the microenvironment in CLL therapy." Blood, 135(15), 1095-1106.
Hillmen, P., et al. (2022). "ALPINE trial: Zanubrutinib vs. ibrutinib in relapsed CLL." Lancet Oncology, 23(2), 207-219.
Wilson, W. H., et al. (2021). "Dual targeting with BTK and BCL-2 inhibitors in lymphomas." Nature Reviews Clinical Oncology, 18(1), 1-14.
Jain, N., et al. (2019). "Resistance mechanisms in BCR-ABL and FLT3 inhibitors." Cancer Research, 79(6), 1213-1223.
DiNardo, C. D., et al. (2021). "Hypomethylating agents plus venetoclax in AML: A paradigm shift." Leukemia, 35(8), 2045-2055.
June, C. H., et al. (2018). "CAR-T cell therapy: The future of cancer treatment?" Science, 359(6382), 1361-1365.
Perna, F., & Sadelain, M. (2020). "Next-generation CAR-T cells: Overcoming current limitations." Nature Reviews Cancer, 20(4), 253-264.
Ghosh, A., et al. (2021). "Trispecific antibodies: A new frontier in immunotherapy." Cell Reports Medicine, 2(6), 100327.
Chen, R., et al. (2019). "Novel immunotherapeutic strategies in hematologic malignancies." Nature Reviews Immunology, 19(5), 321-334. 35-40. Additional references available upon request from PubMed, NEJM, Lancet Oncology, and Blood Journal.
Reference
Cortes, J. E., et al. (2013). "Ponatinib in refractory chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia." New England Journal of Medicine, 369(19), 1783-1796.
Hochhaus, A., et al. (2017). "Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: Results from the BFORE trial." Journal of Clinical Oncology, 36(3), 231-237.
Perl, A. E., et al. (2019). "Gilteritinib or chemotherapy for relapsed FLT3-mutated AML." New England Journal of Medicine, 381(18), 1728-1740.
Seymore, J. F., et al. (2018). "Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia." New England Journal of Medicine, 378(12), 1107-1120.
Moreau, P., et al. (2019). "Venetoclax in relapsed multiple myeloma: BELLINI trial results." Lancet Oncology, 20(12), 1630-1642.
Maude, S. L., et al. (2018). "Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia." New England Journal of Medicine, 378(5), 439-448.
Locke, F. L., et al. (2017). "Phase 1 results of ZUMA-1: Axicabtagene ciloleucel (KTE-C19) for refractory large B-cell lymphoma." Lancet Oncology, 18(1), 44-53.
Schuster, S. J., et al. (2019). "Tisagenlecleucel in adult relapsed/refractory diffuse large B-cell lymphoma." New England Journal of Medicine, 380(1), 45-56.
Ansell, S. M., et al. (2019). "CheckMate 205: Nivolumab for relapsed Hodgkin lymphoma." Journal of Clinical Oncology, 37(15), 1283-1294.
Lesokhin, A. M., et al. (2016). "PD-1 blockade in multiple myeloma: Early results from a phase I trial." Blood, 128(13), 1824-1833.
Viardot, A., et al. (2016). "Blinatumomab for minimal residual disease in acute lymphoblastic leukemia." New England Journal of Medicine, 374(6), 523-532.
Topp, M. S., et al. (2011). "Blinatumomab as a targeted therapy for relapsed B-cell acute lymphoblastic leukemia." Blood, 118(20), 5434-5441.
Connors, J. M., et al. (2018). "Brentuximab vedotin plus chemotherapy for stage III or IV Hodgkin’s lymphoma." New England Journal of Medicine, 378(4), 331-344.
Tilly, H., et al. (2020). "Polatuzumab vedotin with bendamustine and rituximab in relapsed/refractory DLBCL." Journal of Clinical Oncology, 38(2), 155-165.
Sehn, L. H., et al. (2021). "Mosunetuzumab in relapsed/refractory B-cell lymphomas: A bispecific antibody approach." Blood, 138(7), 544-556.
Fenaux, P., et al. (2009). "Azacitidine prolongs survival in higher-risk myelodysplastic syndromes." Lancet Oncology, 10(3), 223-232.
Dombret, H., et al. (2015). "Phase III trial of azacitidine in elderly AML patients." Blood, 126(3), 291-299.
Garcia-Manero, G., et al. (2018). "Decitabine-based epigenetic therapy in myelodysplastic syndromes." Blood Advances, 2(10), 1135-1142.
San-Miguel, J. F., et al. (2013). "Panobinostat for relapsed multiple myeloma: Phase III PANORAMA-1 trial." Lancet Oncology, 14(6), 119-128.
Kirschbaum, M., et al. (2014). "Vorinostat in combination with chemotherapy for relapsed AML." Leukemia Research, 38(12), 1335-1340.
Gabizon, A., et al. (1994). "Liposome-encapsulated doxorubicin: Pharmacokinetics and clinical implications." Cancer Research, 54(4), 987-992.
Barenholz, Y. (2012). "Doxil®—The first FDA-approved nano-drug: Lessons learned." Journal of Controlled Release, 160(2), 117-134.
Sawant, R., & Torchilin, V. (2012). "Challenges in development of targeted liposomal therapeutics." Frontiers in Pharmacology, 3, 141.
Kranz, L. M., et al. (2016). "RNA-based immunotherapy targeting mutated KRAS in AML." Nature Medicine, 22(6), 704-712.
Sahin, U., et al. (2017). "mRNA vaccines for personalized cancer immunotherapy." Nature, 547(7662), 222-226.
Burger, J. A., et al. (2020). "Targeting the microenvironment in CLL therapy." Blood, 135(15), 1095-1106.
Hillmen, P., et al. (2022). "ALPINE trial: Zanubrutinib vs. ibrutinib in relapsed CLL." Lancet Oncology, 23(2), 207-219.
Wilson, W. H., et al. (2021). "Dual targeting with BTK and BCL-2 inhibitors in lymphomas." Nature Reviews Clinical Oncology, 18(1), 1-14.
Jain, N., et al. (2019). "Resistance mechanisms in BCR-ABL and FLT3 inhibitors." Cancer Research, 79(6), 1213-1223.
DiNardo, C. D., et al. (2021). "Hypomethylating agents plus venetoclax in AML: A paradigm shift." Leukemia, 35(8), 2045-2055.
June, C. H., et al. (2018). "CAR-T cell therapy: The future of cancer treatment?" Science, 359(6382), 1361-1365.
Perna, F., & Sadelain, M. (2020). "Next-generation CAR-T cells: Overcoming current limitations." Nature Reviews Cancer, 20(4), 253-264.
Ghosh, A., et al. (2021). "Trispecific antibodies: A new frontier in immunotherapy." Cell Reports Medicine, 2(6), 100327.
Chen, R., et al. (2019). "Novel immunotherapeutic strategies in hematologic malignancies." Nature Reviews Immunology, 19(5), 321-334. 35-40. Additional references available upon request from PubMed, NEJM, Lancet Oncology, and Blood Journal.
Rahul Gangurde
Corresponding author
Assistant professor, MKD college of Pharmacy, Nandurbar
Rahul Gangurde*, C. L. Sindhura, Esther Swapnil Chopade, Sayali Power, Swapnil Chopade, Innovative Therapeutic Approaches and Emerging Targets to Combat Drug Resistance in Hematological Cancers, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 4, 241-250. https://doi.org/10.5281/zenodo.15125607
10.5281/zenodo.15125607
