The pace of therapeutic innovation in hematologic oncology continues to accelerate, moving clinical practice away from broad-spectrum chemotherapy and toward an era of highly personalized, biologically driven treatment. This transformation was the central theme of the 2025 National Comprehensive Cancer Network (NCCN) Annual Congress: Hematologic Malignancies, where leading experts convened to discuss how recent data are crystallizing into new standards of care. Here, we synthesize the key recommendations and potentially practice-changing insights presented for several hematologic malignancies.
Relapsed or Refractory Follicular Lymphoma
“We’re going to see a plateau with these drugs… at the 3- to 4-year mark, maybe around 40% of all patients who received the most benefit will still be in remission.”
—Nancy L. Bartlett, MD
For patients with relapsed or refractory follicular lymphoma in the third-line setting and beyond, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) feature T-cell–engaging therapies, including bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy. Nancy L. Bartlett, MD, of Washington University School of Medicine, outlined the various indications for these immunotherapies.
Nancy L. Bartlett, MD
The NCCN Guidelines include recommendations for the CD20 × CD3 T-cell–engaging bispecific antibodies mosunetuzumab-axgb and epcoritamab-bysp. In trials of patients with at least two prior lines of therapy, mosunetuzumab produced an objective response rate of 78% and a complete response rate of 60%, with a 4-year progression-free survival rate of 39%. Epcoritamab yielded an objective response rate of 82% and a complete response rate of 63%. According to Dr. Bartlett, responses are often seen early, but partial responses are typically not durable.
The NCCN Guidelines include three CD19-directed CAR T-cell therapies: axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. Pivotal trials for these agents demonstrated efficacy. The ZUMA-5 trial showed a 94% objective response rate and a 79% complete response rate with axicabtagene ciloleucel; at 5 years, the progression-free survival rate was 50%. The ELARA trial showed an 86% objective response rate and a 68% complete response rate with tisagenlecleucel; the 4-year progression-free survival rate was 50%. The TRANSCEND FL study showed a 97% objective response rate and a 94% complete response rate with lisocabtagene maraleucel; at 2 years, the progression-free survival rate was 73%. Similar to the bispecifics, partial responses to CAR T-cell therapies are generally not durable. For managing toxicities like cytokine-release syndrome and neurotoxicity, the NCCN Guidelines recommend Pneumocystis jirovecii pneumonia and Varicella-Zoster virus prophylaxis and monthly monitoring of immunoglobulin levels.
Acute Lymphoblastic Leukemia
“We now have many different salvage options that we didn’t have 10 years ago.”
—Ibrahim Aldoss, MD
The treatment of B-cell acute lymphoblastic leukemia (ALL) has been transformed by several novel agents. Ibrahim Aldoss, MD, of the City of Hope National Medical Center, detailed the current treatment paradigm for relapsed or refractory disease.
Ibrahim Aldoss, MD
The bispecific T-cell engager blinatumomab has demonstrated clear superiority over chemotherapy, with the TOWER trial showing improved overall response (44% vs 25%) and median overall survival (7.7 vs 4.0 months). However, Dr. Aldoss emphasized, its efficacy is dependent on disease burden. “If you have extramedullary disease or a high disease burden, maybe blinatumomab is not the right choice,” he advised. He noted that this agent is effective, however, as consolidation therapy for patients in measurable residual disease (MRD)-negative remission.
In contrast to blinatumomab, the efficacy of the antibody-drug conjugate inotuzumab ozogamicin does not appear to be impacted by the quantity of disease, making it a viable option for patients with a high tumor burden. The INO-VATE trial showed a complete remission/complete remission with incomplete count recovery rate of 73.8% vs 30.9% with standard chemotherapy. A key toxicity is sinusoidal obstruction syndrome or veno-occlusive disease, especially when used prior to transplant. “This is why we try to limit how much inotuzumab you give..., and we try to give some washout period between the last dose of inotuzumab and transplant,” Dr. Aldoss explained.
Three CAR T-cell therapies are approved for relapsed or refractory B-cell ALL: tisagenlecleucel (for patients up to age 25), brexucabtagene autoleucel, and obecabtagene autoleucel (for adults). All have demonstrated high rates of complete remission and MRD negativity. The question of whether to proceed to transplant after CAR T-cell therapy remains a topic of debate, and the decision should be individualized.
Managing Cellular Immunotherapy Toxicities in the Ambulatory Setting
“A common theme between T-cell–engaging and CAR T-cell therapies is that there has to be a system in place in the ambulatory setting for adverse effects monitoring.”
—Zachary D. Crees, MD
As cellular immunotherapies move into the outpatient setting, managing their unique toxicities is critical. Zachary D. Crees, MD, of Washington University School of Medicine, emphasized the need for robust ambulatory monitoring systems.
Zachary D. Crees, MD
“With CAR T-cell therapies, the infection risk is higher early on and gets better over time,” Dr. Crees noted. In contrast, with the extended duration of T-cell–engaging therapies, “the cumulative risk of infection tends to go up over time.” Samantha Shenoy, NP, MSN, of the University of California, San Francisco (UCSF), highlighted the high rate of infection with B-cell maturation antigen (BCMA)-targeting T-cell engagers. Key NCCN-supported management strategies for these patients include universal prophylaxis and intravenous immunoglobulin) supplementation. “Every single patient on a BCMA bispecific antibody should be on HSV [herpes simplex virus] and VZV prophylaxis,” Ms. Shenoy stated. For the GPRC5D-targeting agent talquetamab, unique oral and dermatologic toxicities require proactive patient education.
Cytokine-release syndrome (CRS) is the most common toxicity with cellular therapies. According to Mimi Lo, PharmD, BCPS, BCOP, of UCSF, although T-cell engagers have high rates of all-grade CRS, severe cases are rare. In contrast, CAR T-cell therapies are associated with higher rates of severe CRS. “Tocilizumab is considered to be the front-line treatment for patients who have CAR T-cell therapy–associated CRS,” Dr. Lo stated. Immune effector cell–associated neurotoxicity syndrome (ICANS) is less common with these therapies but requires close monitoring. The NCCN Guidelines provide ambulatory management considerations, including ensuring supportive care medications are available and providing robust patient education on home monitoring.
Novel Treatment Options for Hodgkin Lymphoma
“Nivolumab plus AVD is now the standard of care in the United States for patients with advanced [classical Hodgkin lymphoma].”
—Harsh R. Shah, DO
The treatment paradigm for classical Hodgkin lymphoma (cHL) is rapidly evolving beyond the long-standing ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen. According to Harsh R. Shah, DO, of the Huntsman Cancer Institute, recent trials have established new preferred regimens in the NCCN Guidelines for both advanced- and early-stage unfavorable disease.
For patients with advanced-stage disease, the NCCN Guidelines now feature the PD-1 inhibitor nivolumab plus AVD and BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone) as preferred options. This represents a significant shift from the previous PET-adapted ABVD standard from the RATHL trial, which Dr. Shah noted had limitations, with up to 20% of PET-negative patients still relapsing.
Harsh R. Shah, DO
The ECHELON-1 trial is the first study to establish the antibody-drug conjugate brentuximab vedotin plus AVD as superior to ABVD, demonstrating improvement in 5-year progression-free survival (82% vs 75%). A head-to-head trial found nivolumab plus AVD to be superior to brentuximab vedotin plus AVD, with a 10% improvement in 2-year progression-free survival. Dr. Shah highlighted its favorable tolerability and efficacy, particularly in older patients. “What I want to emphasize is that [this treatment] was very effective in patients older than age 60,” he said. Nivolumab plus AVD is now considered a new standard of care in the United States for this patient population. Finally, the BrECADD regimen was found to be more effective and better tolerated than the European standard of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). However, Dr. Shah cautioned, it causes significant hematologic toxicity requiring close monitoring and is not a standard of care in the United States.
Novel agents are also being incorporated into the treatment of difficult-to-treat, early-stage unfavorable cHL. The phase II BREACH trial showed that four cycles of brentuximab vedotin plus AVD followed by radiotherapy improved complete response rates and progression-free survival compared with standard ABVD. Similarly, the phase II NIVAHL trial found that regimens incorporating nivolumab plus AVD yielded high complete remission rates and, after 41 months of follow-up, a 100% overall survival rate. These trials provide evidence to support consideration of incorporating brentuximab vedotin and nivolumab into the upfront management of early-stage unfavorable cHL.
Management of Multiple Myeloma
“If we can get patients to an MRD-negative state, perhaps we are going to create very prolonged, durable remissions before we will have to think about managing relapse.”
—Caitlin Costello, MD
The standard of care for multiple myeloma is rapidly advancing, with quadruplet regimens and cellular therapies reshaping outcomes for patients at all stages of the disease. According to Caitlin Costello, MD, of UC San Diego Moores Cancer Center, quadruplet therapy is the undisputed front-line standard for nearly all newly diagnosed patients, regardless of transplant eligibility.
Caitlin Costello, MD
For transplant-eligible patients, the phase III PERSEUS trial established the CD38 monoclonal antibody daratumumab plus bortezomib, lenalidomide, and dexamethasone as superior to the triplet regimen of VRd, reducing the risk of disease progression or death by 58% and leading to significantly higher rates of MRD negativity. Data from the CEPHEUS and IMROZ trials support using quadruplet regimens in older or less fit patients, demonstrating significant progression-free survival advantages with manageable toxicity. For patients with high-risk cytogenetics, a more potent carfilzomib-based quadruplet may be a potentially superior option, as suggested by the MASTER and GMMG-CONCEPT trials.
Although the DETERMINATION trial confirmed that upfront autologous stem cell transplant continues to offer a significant progression-free survival benefit, Dr. Costello suggested an MRD-adapted approach may be a future option, potentially allowing patients who achieve MRD negativity after induction to safely defer immediate transplant.
For relapsed disease, Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center, emphasized that treatment is stratified by prior therapies. “If the patient has not had an anti-CD38 antibody, this is definitely the time to bring that in,” Dr. Callander advised. Carfilzomib-based triplets like daratumumab plus carfilzomib/dexamethasone or the CD38 monoclonal antibody isatuximab plus carfilzomib/dexamethasone have shown the highest response rates in this setting.
Natalie S. Callander, MD
In the heavily pretreated population of triple-class–refractory disease, T-cell–redirecting therapies are the most effective options, she noted. The BCMA-directed CAR T-cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel have demonstrated unprecedented efficacy, Dr. Callander added, with the KarMMa-3 and CARTITUDE-4 trials validating their use in earlier lines. For a readily available “off-the-shelf” option, bispecific antibodies—including BCMA-targeted agents (eg, elranatamab, linvoseltamab, teclistamab) and the GPRC5D-targeted agent talquetamab—produce high response rates.
Relapsed or Refractory Chronic Lymphocytic Leukemia
“This is a chronic disease, and so in the clinic, we’re seeing patients who might have started their treatment in the 1990s… and have had decades living alongside the diagnosis.”
—Meghan C. Thompson, MD
The management of relapsed or refractory chronic lymphocytic leukemia (CLL) requires individualized sequencing strategies. According to Meghan C. Thompson, MD, of Memorial Sloan Kettering Cancer Center, New York, cytogenetic and molecular testing should be repeated at each relapse, with the exception of IGHV mutational status, which does not change over time.
Meghan C. Thompson, MD
For patients relapsing after chemoimmunotherapy, options include a second-generation covalent Bruton’s tyrosine kinase (BTK) inhibitor (eg, acalabrutinib or zanubrutinib) or fixed-duration venetoclax. “Now, in 2025, acalabrutinib and zanubrutinib are generally preferred,” Dr. Thompson stated, citing superior safety profiles over ibrutinib. The strategy after a novel agent depends on the context.
If treatment with a covalent BTK inhibitor was discontinued because of patient intolerance, switching to an alternate covalent BTK inhibitor is viable. If it was the result of disease progression, however, this may signal biologic resistance, and the preferred next step is switching to a different mechanism, such as a venetoclax-based regimen. If a patient relapses after a long remission following prior venetoclax fixed-duration therapy, venetoclax retreatment is “a viable strategy,” Dr. Thompson confirmed.
For high-risk patients who have experienced disease progression after both a covalent BTK inhibitor and a BCL2 inhibitor, two therapies have become new standards of care: pirtobrutinib and lisocabtagene maraleucel. The noncovalent (reversible) BTK inhibitor pirtobrutinib is effective even with some common resistance mutations to covalent BTK inhibitors, such as BTK C481S mutations. The pivotal BRUIN study showed a median progression-free survival of 16 months in this challenging “double-exposed” population, with excellent tolerability, she noted. Pirtobrutinib is now an NCCN Category 1 recommendation in this setting. The CAR T-cell therapy lisocabtagene maraleucel offers a cellular approach for this heavily pretreated population. The TRANSCEND CLL 004 study showed that the approximately 20% of patients who achieved a complete response with this agent had highly durable remissions. “Patients who had a complete response… do tend to have durable responses,” Dr. Thompson explained.
Acute Myeloid Leukemia
“Differentiation syndrome is not truly an adverse event…. It’s actually an extension of the clinical activity.”
—Naval G. Daver, MD
The treatment paradigm for acute myeloid leukemia (AML) is shifting from decisions based on patient fitness alone to a more sophisticated, biologically driven approach. Experts detailed advancements in risk stratification, the emergence of triplet therapies, and the integration of the novel class of menin inhibitors.
Naval G. Daver, MD
Daniel A. Pollyea, MD, MS
Jessica K. Altman, MD
Daniel A. Pollyea, MD, MS, of the University of Colorado School of Medicine, explained that the primary decision between intensive chemotherapy and lower-intensity venetoclax-based regimens is no longer just about age or comorbidities. The critical question now is whether intensive chemotherapy can be curative for a patient’s specific disease biology; if so, that treatment should be pursued, but if not, it should not necessarily be the default, he commented. Dr. Pollyea emphasized that traditional risk models such as the European LeukemiaNet criteria do not effectively predict outcomes with venetoclax. Newer molecular models may be more useful, identifying variations in IDH1, IDH2, and NPM1 as favorable for venetoclax-based therapy, whereas variations in TP53, KRAS, and PTPN11 tend to be associated with poorer outcomes. This molecular stratification is crucial for guiding the upfront treatment choice, he noted.
For patients treated with lower-intensity regimens, a significant emerging strategy is the use of triplet combinations. Jessica K. Altman, MD, of Northwestern University, highlighted how adding a third, targeted agent to the venetoclax and hypomethylating agent backbone is improving outcomes. For FLT3-mutated AML, she noted, adding a FLT3 inhibitor such as gilteritinib to venetoclax and a hypomethylating agent has produced composite complete remission rates as high as 96% in newly diagnosed patients. As for IDH-mutated AML, triplet combinations incorporating IDH inhibitors are yielding exceptionally high rates of deep, MRD-negative remissions. “This really offers the opportunity to think about treatment-free remissions, scaling back therapy, [and] moving to maintenance,” Dr. Altman commented.
Naval G. Daver, MD, of MD Anderson Cancer Center, described menin inhibitors as a “transformative” new class for AML with KMT2A rearrangements or NPM1 mutations. The recent approval of the menin inhibitor revumenib provides a critical new option for these high-risk subtypes in the relapsed or refractory setting, with a composite remission rate of nearly 50%. Successful use of these targeted agents requires proactive management of unique toxicities, most notably differentiation syndrome, which requires immediate treatment with dexamethasone.
Optimizing First-Line Therapy for Diffuse Large B-Cell Lymphoma
“The overall modest benefit of this trial is because of biological heterogeneity that can be unmasked.”
—Ash A. Alizadeh, MD, PhD
Although the POLARIX trial has established Pola-R-CHP (the antibody-drug conjugate polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone) as a new NCCN Guidelines Category 1 option for first-line diffuse large B-cell lymphoma (DLBCL), its universal application is debated. Ash A. Alizadeh, MD, PhD, of the Stanford Cancer Institute, argued for a precision-medicine approach, contending that the modest overall progression-free survival benefit masks a profound finding driven by the tumor’s molecular subtype. The 5-year follow-up of POLARIX confirmed a modest progression-free survival benefit for Pola-R-CHP over R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) but no overall survival advantage. Dr. Alizadeh’s central argument is that this is explained by the predictive role of the cell of origin classification. The trial’s preplanned analysis revealed that the benefit of Pola-R-CHP was concentrated in patients with the activated B-cell-like (ABC) subtype. Conversely, patients with the germinal center B-cell-like (GCB) subtype derived no demonstrable benefit.
Ash A. Alizadeh, MD, PhD
This difference is highly meaningful in clinical practice, emphasized Dr. Alizadeh. For patients with the ABC subtype, the number needed to treat to prevent one disease progression is four. For the GCB subtype, the number needed to treat is at least 57. This precision strategy is clinically actionable using the widely available Hans algorithm (an immunohistochemistry-based test), a finding validated by large-scale, real-world data. Based on this evidence, Dr. Alizadeh proposed a biomarker-driven algorithm: Pola-R-CHP is the superior therapy for patients with the non-GCB (or ABC) subtype, whereas R-CHOP remains the optimal standard of care for the GCB subtype.
Integrating New Therapies for Chronic Myeloid Leukemia
“Asciminib may be a potential future standard of care, if we can confirm the adverse event profile is as favorable as with imatinib.”
—Gary J. Schiller, MD, FACP
The goals in treating chronic myeloid leukemia (CML) have shifted from ensuring survival to achieving deep molecular responses and, increasingly, treatment-free remission. According to Gary J. Schiller, MD, FACP, of the UCLA Jonsson Comprehensive Cancer Center, the growing number of tyrosine kinase inhibitors allows for a more tailored approach.
Dr. Schiller argued that the first-generation tyrosine kinase inhibitor imatinib remains a valid standard of care. Trials have shown that the overall survival rates with the second-generation tyrosine kinase inhibitors are comparable to those of imatinib. “The main reason to select a second-generation tyrosine kinase inhibitor is to achieve a faster, deeper response, which is important to patients desiring a treatment-free remission,” Dr. Schiller stated.
Gary J. Schiller, MD, FACP
The newest agent, the BCR-ABL tyrosine kinase inhibitor asciminib, has a novel allosteric mechanism and was recently approved for newly diagnosed patients. In the third-line ASCEMBL trial, asciminib demonstrated superior major molecular response compared with bosutinib. In the front-line ASC4FIRST study, asciminib produced deeper and faster responses than standard-of-care tyrosine kinase inhibitors, he noted. Dr. Schiller suggested that asciminib may become a future standard, though its high cost may prove to be a barrier. For now, it is a therapeutic option for patients with resistant disease.
For patients who develop resistance, ABL1 mutation testing is recommended, with the tyrosine kinase inhibitor ponatinib remaining the drug of choice for those with T315I mutations. For treatment-free remission, the NCCN Guidelines provide specific criteria for considering tyrosine kinase inhibitor discontinuation, which includes achieving a deep molecular response for at least 2 years and ensuring the ability for close, frequent molecular monitoring after stopping therapy.
DISCLOSURE: Dr. Bartlett has received grant/research support from ADC Therapeutics, Autolus Therapeutics, BMS/Celgene, Forty Seven, Inc., Genmab/AbbVie, Gilead/Kite Pharma, Janssen, Merck, Millennium Pharmaceuticals, Pharmacyclics, Roche/Genentech, and Seattle Genetics; and has served as a scientific advisor for ADC Therapeutics, Foresight Diagnostics, Genmab/AbbVie, Pfizer/Seagen, Roche/Genentech, and Seattle Genetics. Dr. Aldoss has received grant or research support from AbbVie and Jazz Pharmaceuticals; has served as a scientific advisor for Ascentage Pharma, AstraZeneca, Autolus, Kite Pharma, Novartis, Pfizer, and Takeda Pharmaceuticals North America; has received consulting fees from Adaptive Biotechnologies, Amgen, Jazz Pharmaceuticals, and Servier; and has served on the speakers bureau for Syndax. Dr. Crees has received consulting fees from and served as a scientific advisor for BioLineRx, Gamida Cell, and Vertex Pharmaceuticals. Ms. Shenoy has received a consulting fee from Johnson & Johnson. Dr. Lo has received grant or research support from Jazz Pharmaceuticals. Dr. Shah has received grant or research support from BeOne Medicines (formerly BeiGene), Incyte, Seattle Genetics, and Ipsen; and has received consulting fees from Bristol Myers Squibb, Seattle Genetics, ADCT, and Ipsen. Dr. Costello has received grant or research support from Bristol Myers Squibb, Janssen, and Takeda; and has received honoraria from AstraZeneca, Bristol Myers Squibb, Janssen, Kite Pharma, and Pfizer. Dr. Callander reported no conflicts of interest. Dr. Thompson has received grant or research support from AbbVie, Adaptive Biotechnologies, AstraZeneca, BeOne Medicines, Genentech, Genmab, and Nurix Therapeutics; and has served as a consultant, advisor, or speaker for AbbVie, AstraZeneca, BeOne Medicines, Dava Oncology, Eli Lilly and Company, Genentech, and Janssen.To view full disclosure information for all individuals mentioned in this article, vist ASCOPost.com. To view full disclosure information for all NCCN panel members, visit NCCN.org.
