Can you explain the known mechanism of action of daratumumab, and how it is currently used to treat multiple myeloma?

 Daratumumab is an anti-CD38 immunoglobulin (Ig) G1 monoclonal antibody-the first to be approved for the treatment of relapsed/refractory multiple myeloma. About a decade ago, preclinical studies showed that targeting CD38 might be feasible, and last November, two clinical trials showed significant activity of single-agent daratumumab, leading to US Food and Drug Administration approval of the drug. The first trial-GEN501-was a phase I trial, with an expansion phase II trial, and the second was the SIRIUS phase II trial. In both studies, as a single agent, daratumumab showed an overall response rate of approximately 30%, higher than any other previous single-agent proteasome inhibitor or immune-modulator drug. The effect of daratumumab is through three different mechanisms: antibody-dependent cytotoxic activity; complement-dependent cytotoxicity; and antibody-dependent cellular phagocytosis. Apart from that, there is some new immune-directed activity that is worth discussing.

 You are referring to a study published this year in the journal 

 that showed that daratumumab not only exerted its effects through CD38-expressing cells, but also boosted the number and activity of cytotoxic T cells and helper T cells. Can you describe the study and how it was conducted?

 This study by Krejcik et al[1] tells us about the importance of biomarkers in the research setting. Nearly all studies collect biologic samples, including biopsies, so that we have an idea of why the drug works, or in whom the drug works, and whether we have biomarkers that we can relate to the drug. In this study, peripheral blood and bone marrow samples were collected before and after treatment, during the trial, and at the time of progression. The samples were analyzed for different immune factors and assessed for functional activity of the immune cells. The researchers looked at the microenvironment, as well as various T cells and immune cells such as regulatory B cells, myeloid-derived suppressor cells (MDSCs), and also a novel T-regulator cell expressing CD38, and discovered that immune action was being prohibited on these multiple myeloma cells. Daratumumab helped improve the tumor microenvironment by enhancing the immune response, and actually reduced T-regulator cells, MDSCs, and B-regulatory cells at the same time that it helped expand helper and cytotoxic T cells. In addition, there was also an increase of functional activity of these cells, which had more alloreactive functions.

In the current era of immune therapies, such as cytotoxic T-lymphocyte–associated antigen 4, programmed death 1, and programmed death ligand 1 antibodies that have been used across different solid tumors and hematologic malignancies, there has been significant activity of this type of immune mobilization. We know from previous studies that multiple myeloma also has immune dysfunction, including immune evasion through expression of various immune checkpoints, elevated immune receptors and activity, and immune suppression through MDSCs.

 Based on this work, what further studies or trials would you like to see next on this newly identified activity?

In this setting, we see a similar activity as with immune checkpoint inhibitors, which is immune enhancement. The significance of daratumumab is that it also targets CD38-positive plasma cells. This “dual action”-where the tumor is targeted and there is immune enhancement against the tumor-is a very elegant pro–immune system action against the tumor cells. Therefore, it’s a no-brainer that we should combine checkpoint inhibitors to see if this immune enhancement is stronger toward myeloma cells. Also, with pomalidomide and thalidomide, which are immune-modulating drugs that are the standard or backbone of myeloma treatment, there is the question of whether a combination of these drugs may enhance the immune action against myeloma cells. The most important strategy is to use daratumumab in earlier stages of myeloma, like monoclonal gammopathy of undetermined significance or smoldering myeloma, to see if we can mobilize the immune system in a way that can achieve longer antimyeloma control.

Is there potential to use this antibody for other hematologic malignancies or solid tumors?

 If daratumumab is mobilizing the immune system in a way that reduces the B- and T-regulatory cells (that inhibit T-cell function) and MDSCs, whether it can act as another immune checkpoint inhibitor and be combined with other antibodies or cytotoxic therapies in various other solid tumors is an open question. I believe we will see these types of studies with daratumumab in the future.

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

 Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384-94.

Articles

In this interview we discuss the mechanisms of daratumumab, how it is currently used for the treatment of multiple myeloma, and how it might be used in the future.

Amitkumar Mehta on the Immunomodulating Effects of Targeted Therapy for Multiple Myeloma

In the recent era of effective systemic therapies for melanoma, the provocative question of whether isolated limb perfusion (ILP) still plays a role in the treatment of patients with in-transit melanoma metastases is timely and relevant. In their systematic review of ILP treatment considerations and response rates, Drs. GrÃ¼nhagen and Verhoef provide a balanced assessment of the benefits and drawbacks of regional therapy approaches.[1]

ILP is a venerable therapy with which clinicians have more than 50 years of experience and for which there are measures known to limit the predictable toxicities. It has evolved into an effective modality that produces a complete response (CR) rate of about 60%, with half of those responses being durable. Since ILP is an “old” approach using an “old” chemotherapy agent (melphalan), it is easy to dismiss this technique in favor of emerging state-of-the-art systemic options, including small-molecule inhibitors and checkpoint blockade immunotherapy. In terms of CR rates, ILP remains superior to all other approaches, but is limited to a select group of patients with extremity in-transit melanoma metastases. When considering cost and overall outcome, a single treatment with ILP appears to represent just a fraction of the expenditure associated with systemic therapies that are typically continued for a prolonged period of time, or even indefinitely. The cumulative data presented by the authors emphatically suggests that there is a definite role for ILP in select melanoma patients with regional disease. However, the real question is how to employ ILP, perhaps in combination with other therapies, to either boost in-limb responses or influence systemic recurrence rates and overall survival.

Other than the inclusion of tumor necrosis factor (TNF), replacement chemotherapies or additive agents have been lacking in the field of regional therapies. While the authors provide strong data and a compelling rationale for the use of TNF during ILP, due to an often-criticized clinical trial,[2] TNF is not utilized in this setting in the United States. TNF improves response rates, but patients require close monitoring for systemic leak, which can be profound. Ultimately, drugs designed to take advantage of the hyperthermia and localized delivery characteristic of ILP may prove fruitful, and ILP combinations may represent a unique niche in which to test novel agents for their ability to cause high rates of CR, which would make them potentially interesting for further systemic development.

The combination of ILP and immunotherapy is particularly appealing as a means of influencing disease-free survival and potentially overall survival. Ongoing clinical trials are evaluating the application of anti–cytotoxic T-lymphocyte–associated antigen 4 combined with ILP or isolated limb infusion (ILI) (ClinicalTrials.gov identifiers: NCT02094391 and NCT02115243). Theoretically, these approaches would take advantage of the high rates of in-limb response to treatment with ILP and simultaneously generate a systemic immune response against any occult micrometastases. Accordingly, GrÃ¼nhagen and Verhoef identify this as an area ripe for research in specialized melanoma centers. For example, the optimal timing of immunotherapy before or after ILP or ILI, the duration of treatments, the potential for synergy and dose reduction, and the unique toxicities encountered are completely unknown. Further, the emergence of other checkpoint inhibitors, small-molecule inhibitors, viral oncolytics (eg, talimogene laherparepvec, known as T-VEC), and other injectable agents (eg, PV-10) is exciting, but new agents need to be incorporated into therapeutic protocols in a rational way.

In their review, Drs. GrÃ¼nhagen and Verhoef rightly bring attention to the superior results historically achieved with ILP in comparison with the responses seen with current systemic therapies. Overall, the greatest challenges facing clinicians with regard to the treatment of in-transit melanoma metastases are selecting the appropriate patients for a regional therapy approach, and recognizing that ILP still affords unmatched responses despite the building excitement associated with modern systemic therapies.

The authors have no significant interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

 GrÃ¼nhagen DJ, Verhoef C. Isolated limb perfusion for stage III melanoma: Does it still have a role in the present era of effective systemic therapy? Oncology (Williston Park). 2016;30:1045-52.

 Cornett WR, McCall LM, Petersen RP, et al. Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020. J Clin Oncol. 2006;24:4196-201.

In the recent era of effective systemic therapies for melanoma, the provocative question of whether isolated limb perfusion still plays a role in the treatment of patients with in-transit melanoma metastases is timely and relevant.

New Does Not Always Mean Better: Isolated Limb Perfusion Still Has a Role in the Management of In-Transit Melanoma Metastases

When Hodgkin's disease, now referred to as Hodgkin lymphoma, was first described in 1853, it was a deadly disease. Patients usually died within months of diagnosis, and treatment was focused on improving patient comfort. In 1954, an era where only 5% of patients with Hodgkin lymphoma survived, Drs. Henry Kaplan and Edward Ginzton invented the first medical linear accelerator in the Western Hemisphere to deliver therapeutic radiotherapy (RT) with improved accuracy and potency, leading to curative outcomes in a group of patients with Hodgkin lymphoma.[1] Around this time, DeVita et al demonstrated the first curative combination chemotherapy in cancer, the MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) regimen for patients with Hodgkin lymphoma.[2] The concept of combined-modality treatment was advanced by Dr. Kaplan and Dr. Saul Rosenberg, who demonstrated that extended-field RT and combination chemotherapy could be curative for Hodgkin lymphoma patients.[3,4] Despite these advances, the late toxicities of chemotherapy and increased risk of secondary malignancies with RT have threatened the survival rates and quality of life of Hodgkin lymphoma patients. What is the cost of curing Hodgkin lymphoma, particularly in our young population?

In this issue of ONCOLOGY, Overholser and colleagues review a woman’s risk of developing breast cancer after receiving RT to the chest, and identify strategies to reduce this risk.[5] Although the authors cite data suggesting no significant differences between RT-induced breast cancers compared with sporadic breast cancers-except for an increased risk of bilateral breast cancer-our clinical experience, along with more recent studies, suggests otherwise. Broeks et al analyzed gene expression profile data to query whether differences in molecular subtype exist between sporadic breast cancers and breast cancers associated 1with RT exposure.[6] Breast cancers after Hodgkin lymphoma were enriched for the basal and human epidermal growth factor receptor 2 (HER2)-enriched tumor subtypes (50% overall) and were found to have significantly higher expression of the Ki-67 proliferation marker compared with controls, as well as a profile of chromosomal instability. Using data from the Stanford Hodgkin’s Disease Database from 1966 to 1999, Horst et al retrospectively reviewed 147 patients with a history of Hodgkin lymphoma and chest RT who subsequently developed breast cancer.[7] At our center, among patients with invasive breast cancer and complete pathologic information (n = 51), breast cancers after Hodgkin lymphoma were almost three times more likely to be triple-negative compared with age-matched controls (39% vs 14%). In this cohort, 49% had estrogen receptor (ER)-negative and progesterone receptor (PR)-negative disease, and only 14% were HER2-positive. Meattini et al also showed elevated rates of hormone receptor–negative cancers (28%) compared with sporadic cases (13%) in a series of 39 patients.[8] Taken together, these data suggest RT-associated breast cancers have a more aggressive biology compared with sporadic cases.

These results challenge whether women at risk for secondary breast cancer after chest RT for Hodgkin lymphoma should be universal candidates for chemopreventive agents, such as selective estrogen receptor modulators or aromatase inhibitors, which are only effective in preventing ER-positive tumors. Overholser and colleagues discuss the role of endocrine therapy to reduce risk for breast cancer, and cite interesting data from patients who developed premature ovarian failure due to ovarian irradiation or alkylating chemotherapeutic agents, which demonstrates that these patients were at decreased risk for developing subsequent breast cancer.[9] Data from large studies of chemoprevention in breast cancer reveal that this strategy is less effective in patients at risk for developing hormone receptor–negative tumors. Thus, if the breast cancers occurring in women post RT have elevated rates of ER and PR negativity, then women could be unnecessarily exposed to agents such as tamoxifen and could be potentially put at elevated risk for post–Hodgkin lymphoma treatment–related toxicity. Most importantly, patients who received chest RT are at greater risk of cardiac complications, including coronary artery disease, valvular heart disease, congestive heart failure, and pericardial disease. Heidenreich et al evaluated women who received prior RT doses > 35 Gy to the mediastinum for the presence of occult coronary artery disease and discovered elevated rates of stress-induced perfusion defects or wall motion abnormalities on echocardiogram.[10] Moreover, patients had a significantly elevated relative risk of mortality from myocardial infarction, ranging between 7.3 and 8.1, depending on the length of time since radiation exposure. Given potential risks of thrombosis with drugs like tamoxifen, caution must be taken when evaluating patients’ eligibility for this type of chemoprevention strategy.

Although increased hormone receptor negativity in RT-associated breast cancer could appear to limit therapeutic options, the unique mutational profile of RT-associated breast cancers could also potentially confer susceptibility to certain therapies. Radiation is known to damage DNA and cause chromosomal instability. As previously noted, Broeks et al demonstrated that RT-associated breast cancers have a profile of chromosomal instability, and in other contexts, this has been found to be associated with increased host antitumor immunity.[6,11] Looking ahead, the DNA damage and potentially increased mutation rate in RT-associated breast cancer may be linked with responsiveness to immunotherapies, such as immune checkpoint inhibitors. In melanoma, an increase in overall mutational and neoantigen load-novel tumor-specific antigens that can be recognized by the immune system-was associated with clinical benefit from checkpoint blockade.[12] Cancers that respond the most favorably to checkpoint inhibitors include non–small-cell lung cancer, largely caused by chronic exposure to carcinogens in cigarette smoke, and melanoma, largely caused by exposure to ultraviolet light.[13] In breast cancer, preliminary studies show that inhibition of programmed death 1 (PD-1) and PD ligand 1 (PD-L1) has been associated with clinical activity in metastatic triple-negative breast cancer,[14,15] with multiple trials ongoing in this space. An exploration of the role of immunotherapy in RT-induced breast cancers and other RT-associated malignancies is an interesting topic and worthy of further investigation.

In summary, curative therapy, including chest RT for Hodgkin lymphoma, is associated with a definitively increased risk of breast cancer, most often manifesting approximately 20 years after treatment. These breast cancers tend to be more aggressive, with greater frequency of hormone receptor negativity and potential HER2 positivity. This breast cancer phenotype has implications for chemopreventive strategies in at-risk Hodgkin lymphoma survivors, and a careful risk:benefit analysis should be discussed with patients considering this approach. Overholser and colleagues nicely summarize the current state of knowledge in this important area.[5] As RT delivery methods continue to improve and RT use for this disease decreases, it is our hope that the incidence of RT-associated breast cancer following curative treatment for Hodgkin lymphoma will decline.

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article

 Canellos GP, Rosenberg SA, Friedberg JW, et al. Treatment of Hodgkin lymphoma: a 50-year perspective. J Clin Oncol. 2014;32:163-8.

 DeVita VT Jr, Serpick AA, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med. 1970;73:881-95.

 Kaplan HS, Rosenberg SA. Extended-field radical radiotherapy in advanced Hodgkin’s disease: short-term results of 2 randomized clinical trials. Cancer Res. 1966;26:1268-76.

 Rosenberg SA, Kaplan HS. The management of stages I, II, and III Hodgkin’s disease with combined radiotherapy and chemotherapy. Cancer. 1975;35:55-63.

 Overholser L, Shagisultanova E, Rabinovitch RA, et al. Breast cancer following radiation therapy for Hodgkin lymphoma: clinical scenarios and risk-reducing strategies. Oncology (Williston Park). 2016;30:1063-70.

 Broeks A, Braaf LM, Wessels LF, et al. Radiation-associated breast tumors display a distinct gene expression profile. Int J Radiat Oncol Biol Phys. 2010;76:540-7.

 Horst KC, Hancock SL, Ognibene G, et al. Histologic subtypes of breast cancer following radiotherapy for Hodgkin lymphoma. Ann Oncol. 2014;25:848-51.

 Meattini I, Livi L, Saieva C, et al. Breast cancer following Hodgkin’s disease: the experience of the University of Florence. Breast J. 2010;16:290-6.

 Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. 2003;290:465-75.

 Heidenreich PA, Schnittger I, Strauss HW, et al. Screening for coronary artery disease after mediastinal irradiation for Hodgkin’s disease. J Clin Oncol. 2007;25:43-9.

 Strickland KC, Howitt BE, Shukla SA, et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget. 2016;7:13587-98.

 Van Allen EM, Miao D, Schilling B, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350:207-11.

 Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-8.

 Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Cancer Res. 2015;75(suppl):abstr 2859.

 Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Cancer Res. 2015;75(suppl):abstr S1-09.

Curative therapy, including chest RT for Hodgkin lymphoma, is associated with a definitively increased risk of breast cancer, most often manifesting approximately 20 years after treatment. These breast cancers tend to be more aggressive, with greater frequency of hormone receptor negativity and potential HER2 positivity. 

Breast Cancer After Hodgkin Lymphoma: The Price of Success

The Pendulum Swings Again: Time to Reassess the Role of ASCT in First Complete Remission

More recent insights into mantle cell lymphoma biology and resultant clinical trials have advanced our understanding of this disease, and treatment outcomes have improved.[1,2] Further, newer agents such as bortezomib, lenalidomide, and ibrutinib, as well as a clearer picture of the molecular biology, have significantly changed our approach to management.[3-6]

High-dose therapy with transplant in first complete remission

Initial attempts at more aggressive immunochemotherapy with rituximab (R) and a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or with purine analog–containing regimens, improved the response and time to treatment failure, but did not have an impact on overall survival.[7,8]

Therefore, in an effort to improve patient outcomes, over the last 2 decades, investigators in the United States and Europe have explored algorithms for intensified treatment, including high-dose chemotherapy followed by autologous stem cell rescue-a strategy that had proven to be effective in patients with diffuse large B-cell lymphoma. Most recently, a project by the European Mantle Cell Lymphoma Network and the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation studying the role of autologous stem cell transplantation (ASCT) and allogeneic stem cell transplantation in mantle cell lymphoma reached consensus in support of ASCT as standard first-line consolidation therapy, but concluded that it should not be used before the patient has achieved a complete or partial response.[9]

However, because these regimens also incorporated rituximab and cytarabine, drugs that on their own resulted in improved outcomes in mantle cell lymphoma,[10] there are some limitations to interpretation of these phase II transplant trials.[11-14]

Intensive chemotherapy: cytarabine and rituximab

Romaguera and colleagues at the MD Anderson Cancer Center published and then updated data in a single-institution study of 97 patients treated with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper-CVAD) without transplant.[15,16] The initial analysis in the nontransplanted patients indicated that with a median follow-up of 40 months, the 3-year failure-free survival (FFS) and overall survival (OS) rates were 64% and 82%, respectively, with no plateau in the survival curves. For patients < 65 years of age, the 3-year FFS rate was 73%.[15] At 10 years (median, 8 years), the median OS for all patients was not reached, and median time to failure (TTF) was 4.6 years.[16] For patients < 65 years old, the median TTF was 5.9 years. Patients > 65 years old, who are generally not considered good candidates for transplant, did not do as well.[17] In the pre-rituximab era, the MD Anderson group also looked at 45 patients who had been treated with hyper-CVAD (without rituximab) followed by ASCT. Of these patients, 25 had no prior therapy, and this group had an OS rate of 92% at 3 years and an event-free survival (EFS) rate of 72%, while the 20 previously treated patients had OS and EFS rates of 25% and 17%, respectively.[18]

In a retrospective analysis from the National Comprehensive Cancer Network, LaCasce et al found that the outcomes were identical for patients treated with R-hyper-CVAD with vs without transplant, and only patients treated with R-CHOP appeared to benefit from transplant.[19]

In 1996, at the dawn of the rituximab era, to address the issue of the role of transplant in first remission, the European Mantle Cell Lymphoma Network initiated a randomized trial of CHOP (without rituximab or cytarabine) followed by either interferon maintenance or myeloablative radiochemotherapy (high-dose cyclophosphamide + 12-Gy total body irradiation) and ASCT. This remains the only trial to compare transplant vs no transplant in patients with mantle cell lymphoma in first complete remission, and it was completed before clinical use of cytarabine or maintenance therapy with rituximab was widespread. Patients in the transplant group had longer durations of progression-free survival, but at first analysis there was no difference in OS outcomes between the groups.[8]

An interim analysis that was presented but not published (Hoster, 2009 American Society of Hematology Annual Meeting) suggested that transplant conferred a survival advantage (

 = .034), but the final analysis has not been completed (Dreyling, personal communication). These data, from the era before treatment of mantle cell lymphoma with rituximab or cytarabine, suggest that even when the control treatment is less than adequate by today’s standards, high-dose chemoradiotherapy and ASCT have not been shown to improve overall survival. Final analysis of these data in a manuscript format should be forthcoming. Despite the lack of convincing data, subsequent studies-all phase II nonrandomized trials-incorporated high-dose chemotherapy followed by transplant as part of the treatment algorithm for patients in first complete remission, elevating transplant to a standard of care with no compelling data[9,20] and despite late recurrences.[21]

What other alternatives exist for patients affected by this chronic disease? In 2006, Forstpointner and colleagues examined the role of maintenance rituximab and found its use was associated with prolonged progression-free survival.[22] The European Mantle Cell Lymphoma Network randomized patients over 65 years of age who were not candidates for transplant to receive either R-CHOP or a purine analog–containing regimen (rituximab, fludarabine, and cyclophosphamide) and then to lifetime rituximab maintenance vs interferon maintenance. They found that the remission duration was 23 months in the interferon arm and was not reached at the time of publication in the rituximab arm.[23] Further, in the Nordic trials, Andersen et al made a very strong case for rituximab maintenance therapy. They published data showing that, post transplant, when patients with an apparent complete response were monitored by disease-specific primers, of 36 patients who had molecular relapse without signs of clinical relapse, 26 had undergone preemptive treatment with rituximab. Of these 26 patients, 24 (92%) reverted to polymerase chain reaction–negative status for a median duration of 1.5 years.[12]

These findings suggest that a targeted maintenance strategy has validity, but when disease-specific primers are not routinely available, it is rational, based on these data, to conclude that regular maintenance therapy may indeed provide benefit. This argument is made even stronger by recent data suggesting that in a randomized trial by the Lymphoma Study Association (known as the Lysa group), maintenance rituximab following transplant results in prolonged disease-free survival compared with transplant without maintenance.[24] Together with the other previously described data, this raises the question of whether transplant benefits only a very select group of patients. Indeed, recent reviews on the subject call into serious question the value of transplant in mantle cell lymphoma patients in first complete remission.[2,25]

Management strategies for patients with mantle cell lymphoma continue to demonstrate pendulum-like swings between those appropriate for low-grade lymphoma, and those appropriate for very aggressive lymphoma. As research advances, it now appears that we are dealing with not one disease entity but several diseases; this will be delineated more clearly as we continue to uncover relevant molecular and clinical features.[26] Our approach in the future will be dictated by a better understanding of biology; until then, we cannot mandate aggressive treatment (eg, transplant) or nonaggressive treatment as the standard for all patients. There will be some patients who can be observed as an alternative to immediate treatment[27,28]; some patients (with blastoid variants or high-risk molecular features) who may require intensive therapy including allogeneic or autologous transplant and a maintenance regimen[29-31]; and some who may be treated with immunochemotherapy or targeted agents (ibrutinib), with or without maintenance, and without transplant. The use of patient-specific molecular probes to detect disease after therapy will ultimately drive our treatment algorithms and will enable us to follow a more personalized and rational therapeutic approach to the management of patients with mantle cell lymphoma.

The author has no significant interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

 Gordon LI, Bernstein SH, Jares P, et al. Recent advances in mantle cell lymphoma: report of the 2013 Mantle Cell Lymphoma Consortium Workshop. Leuk Lymphoma. 2014;55:2262-70.

 Dreyling M, Ferrero S; European Mantle Cell Lymphoma Network. The role of targeted treatment in mantle cell lymphoma: is transplant dead or alive? Haematologica. 2016;101:104-14.

 El Halabi L, Ghez D, Ribrag V. Novel targeted therapeutics for mantle cell lymphoma – What’s on the horizon? Expert Rev Hematol. 2016;9:271-81.

 Robak T. Novel therapies under investigation for mantle cell lymphoma. Expert Opin Investig Drugs. 2016;25:375-80.

 Ruan J, Leonard JP. Lenalidomide plus rituximab for mantle-cell lymphoma. N Engl J Med. 2016;374:793.

 Simonsen AT, Schou M, SÃ¸rensen CD, et al. SOX11, CCND1, BCL1/IgH and IgH-VDJ: a battle of minimal residual disease markers in mantle cell lymphoma? Leuk Lymphoma. 2015;56:2724-7.

 Forstpointner R, Dreyling M, Repp R, et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004;104:3064-71.

 Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005;105:2677-84.

 Robinson S, Dreger P, Caballero D, et al. The EBMT/EMCL consensus project on the role of autologous and allogeneic stem cell transplantation in mantle cell lymphoma. Leukemia. 2015;29:464-73.

 Lefrere F, Delmer A, Suzan F, et al. Sequential chemotherapy by CHOP and DHAP regimens followed by high-dose therapy with stem cell transplantation induces a high rate of complete response and improves event-free survival in mantle cell lymphoma: a prospective study. Leukemia. 2002;16:587-93.

 Gianni AM, Magni M, Martelli M, et al. Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen). Blood. 2003;102:749-55.

 Andersen NS, Pedersen LB, Laurell A, et al. Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma. J Clin Oncol. 2009;27:4365-70.

 Dreyling M, Hoster E, Bea S, et al. Update on the molecular pathogenesis and clinical treatment of mantle cell lymphoma (MCL): minutes of the 9th European MCL Network conference. Leuk Lymphoma. 2010;51:1612-22.

 Damon LE, Johnson JL, Niedzwiecki D, et al. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009;27:6101-8.

 Romaguera JE, Fayad L, Rodriguez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23:7013-23.

 Romaguera JE, Fayad LE, Feng L, et al. Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Br J Haematol. 2010;150:200-8.

 Romaguera JE, Khouri IF, Kantarjian HM, et al. Untreated aggressive mantle cell lymphoma: results with intensive chemotherapy without stem cell transplant in elderly patients. Leuk Lymphoma. 2000;39:77-85.

 Khouri IF, Romaguera J, Kantarjian H, et al. Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol. 1998;16:3803-9.

 LaCasce AS, Vandergrift JL, Rodriguez MA, et al. Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: an analysis from the NCCN NHL Database. Blood. 2012;119:2093-9.

 Delarue R, Haioun C, Ribrag V, et al. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d’Etude des Lymphomes de l’Adulte. Blood. 2013;121:48-53.

 Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 2012;158:355-62.

 Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006;108:4003-8.

 Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012;367:520-31.

 Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab maintenance versus wait and watch after four courses of R-DHAP followed by autologous stem cell transplantation in previously untreated young patients with mantle cell lymphoma: first interim analysis of the phase III prospective Lyma trial, a Lysa study. Blood. 2014;124:abstr 146.

 Geisler CH. Autologous transplantation and management of younger patients with mantle cell lymphoma. Best Pract Res Clin Haematol. 2012;25:211-20.

 Cheah CY, Seymour JF, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34:1256-69.

 Furtado M, Rule S. Indolent mantle cell lymphoma. Haematologica. 2011;96:1086-8.

 Martin P. Watching and waiting in mantle cell lymphoma. Clin Adv Hematol Oncol. 2013;11:794-5.

 Laszlo T, Matolcsy A. Blastic transformation of mantle cell lymphoma: genetic evidence for a clonal link between the two stages of the tumour. Histopathology. 1999;35:355-9.

 M’Kacher R, Farace F, Bennaceur-Griscelli A, et al. Blastoid mantle cell lymphoma: evidence for nonrandom cytogenetic abnormalities additional to t(11;14) and generation of a mouse model. Cancer Genet Cytogenet. 2003;143:32-8.

 Kasamon YL, Burns KH. Blastic transformation of mantle cell lymphoma. Blood. 2012;120:2359.

Management strategies for patients with mantle cell lymphoma continue to demonstrate pendulum-like swings between those appropriate for low-grade lymphoma, and those appropriate for very aggressive lymphoma.

COUNTERPOINT: The Role of Stem Cell Transplantation in Mantle Cell Lymphoma

The management of mantle cell lymphoma has evolved dramatically since 1994, when the Revised European-American Lymphoma Classification recognized it as a separate disease entity. This was based not only on the distinct molecular features (hallmark t(11;14) translocation) and immunophenotype of mantle cell lymphoma but also on its distinct clinical course, with much poorer outcomes than those of other patients with so-called indolent lymphomas. Such challenges led to exploration of novel approaches, contributing to an improvement in median overall survival (OS) over the last 4 decades, from 2.5 years in the late 1970s to 4.5 years in the mid-1990s and 5 to 7 years or longer in the late 2000s.[1,2] Several factors underlie this continued upswing in survival outcomes for patients with mantle cell lymphoma.These range from better supportive care; to the use of dose-intensive therapy (DIT), leading to prolonged disease-free intervals well in excess of 5 to 7 years; to the development of promising novel therapies for a disease in which patients commonly become chemoresistant in the relapsed setting.[3]

The mantle cell lymphoma treatment landscape is changing rapidly, based on novel combinations, including biologics, as well as on a better understanding of the impressive molecular diversity of this disease.[4] With the availability of new therapeutic options, it is naturally tempting to revisit-not abandon-previous milestones. Although the optimal treatment of mantle cell lymphoma remains controversial, some cornerstone therapies have emerged that have extended the duration of first complete remission, a critical factor for durable long-term clinical benefit in mantle cell lymphoma. These include the addition of rituximab to induction therapy regimens, as well as the use of cytarabine-based induction and DIT, with or without autologous stem cell transplantation (ASCT) consolidation.

In a randomized prospective trial by the German Low-Grade Lymphoma Study Group, the addition of rituximab (R) to a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (without ASCT) clearly increased the overall response rate, complete response (CR) rate, and time to treatment failure in patients with mantle cell lymphoma, but R-CHOP had no significant impact on progression-free survival (PFS; median rate of 25% at 2 years) or OS compared with CHOP alone.[5] Based on the poor results of standard induction therapy, the natural shift was to use high-dose therapy (HDT) followed by ASCT as consolidation in first remission. The initial favorable results of smaller phase II trials were confirmed by a large randomized German trial in which patients responding to CHOP were randomized between maintenance interferon (IFN-Î±) and HDT-ASCT.[6] While there was a significant improvement of both PFS and duration of response in favor of the HDT-ASCT consolidation arm, there was no difference in OS outcomes, likely because of the crossover design of the trial.

Several subsequent studies of DIT/HDT have repeatedly confirmed an extension of the median PFS by well over 5 years.[7-9] In contrast, the median PFS with R-CHOP remains in the 14- to 18-month range, even in the recent LYM-3002 phase III trial in patients not eligible for HDT-ASCT (R-CHOP vs R-CHOP + bortezomib,[10] with 244 patients per arm). Although the combination of bendamustine plus rituximab (BR) was reported to be superior to R-CHOP (median PFS, 22 months vs 35 months; 

 = .06) in the mantle cell lymphoma cohort (92 patients) from the Study Group for Indolent Lymphomas trial,[11] superiority of BR over R-CHOP was not suggested by results of the attempted confirmatory BRIGHT trial in the United States (with the exception of the CR rate, but the control arm had pooled both patients treated with R-CHOP and patients treated with R-CVP [cyclophosphamide, vincristine, and prednisone]).[12] BR was piloted by the Southwest Oncology Group as induction therapy prior to HDT, with promising updated results from a small trial that was interrupted because of failure to mobilize stem cells in the R-hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) arm (which was done only after cycle 1A and 1B).[13] Typically, DIT/HDT strategies are associated with much higher CR rates-about 55% prior to ASCT and over 85% to 90% post ASCT (vs a CR rate of approximately 30% for patients treated with R-CHOP or BR); as might be expected, these results translate into much more durable remissions and disease-free intervals.

It also became clear through the use of these DIT/HDT strategies that incorporating cytarabine as part of induction therapy pre-ASCT was critical. The benefit of cytarabine, as part of the DHAP regimen (dexamethasone, high-dose cytarabine, and cisplatin), was initially shown by the French Groupe d’Ãtude des Lymphomes de l’Adulte (R-CHOP/R-DHAP → ASCT, which tripled the CR rate and produced a median event-free survival [EFS] time of 83 months).[14] The initial impressive results of the Nordic MCL2 trial (maxi-CHOP alternating with cytarabine → ASCT) were recently updated with a median PFS of 8.5 years and a median OS of 12.7 years (at a median follow-up of 11.4 years) in an intent-to-treat analysis.[15]

The benefit of high-dose cytarabine was definitively proven by a large and remarkable phase III study from the European Mantle Cell Lymphoma Network, in which more than 400 patients were randomized to treatment with R-CHOP/R-DHAP (alternating for 6 cycles) followed by HDT (using cytarabine plus melphalan in combination with total body irradiation) vs R-CHOP for 6 cycles followed by HDT (using cytarabine in combination with total body irradiation).[8] The results showed the cytarabine-containing arm to be superior, in terms of time to treatment failure (the primary study endpoint), with a 30% reduction in the risk of progression, and this was verified across all Mantle Cell Lymphoma International Prognostic Index (MIPI) subgroups. The superior results were attributed to the quality of response seen in the high-dose cytarabine arm, which showed much earlier CRs and a higher CR rate compared with the R-CHOP arm, translating into a longer duration of first response and better treatment outcomes.

The molecular CR rate post induction was 83% in the cytarabine arm vs 51% in the control arm (

 < .0001), translating to a new standard for DIT/HDT in frontline therapy for mantle cell lymphoma. In addition, built-in assessments of minimal residual disease (MRD) in this study revealed the profound impact on outcome of achieving negative MRD status (ie, a molecular CR).[8] Indeed, given that several studies have now shown MRD status to be predictive of outcome across the board, negative MRD will likely become a key endpoint in future mantle cell lymphoma trials.[16]

The agents used for induction in the Nordic MCL2 trial regimen (R-maxi-CHOP alternating with high-dose cytarabine) are not very different from the regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper-CVAD), alternating with methotrexate and high-dose cytarabine, another dose-intensive regimen frequently used in mantle cell lymphoma patients younger than 65 years (without ASCT consolidation). The initial experience with R-hyper-CVAD in a study of 97 patients, one-third of whom were over 65 years old, showed a CR rate of 87% and a 3-year failure-free survival rate of 73% in the under-65 group,[17] consistent with the results seen with ASCT consolidation. In a recent update with 15-year follow-up,[18] the median OS exceeded 10 years for all patients, while about one-third of the patients 65 years and older were still in their first remission. The R-hyper-CVAD regimen has been used as induction pre-ASCT with very strong results,[19] although it is not clear in this population, particularly in patients achieving a CR, that the HDT-ASCT consolidation is needed. This question is being addressed by the ongoing TRIANGLE study in Europe, which aims to evaluate ibrutinib in the frontline setting, including a randomization of HDT vs maintenance ibrutinib post induction.

Although no one would argue about the progress achieved by the use of DIT/HDT compared with standard therapy, such dosing strategies are not always feasible in the mantle cell lymphoma population, whose median age at diagnosis is in the mid to late 60s. However, the presence of comorbidities-not just age-should guide patient management decisions, since selected patients over 65 years of age can enjoy clinical outcomes similar to those achieved in younger patients, even following treatment with HDT-ASCT.[20] In reality, such patients are typically excluded from trials, and it then becomes important to evaluate results seen in real-world clinical practice, where unfortunately, overall outcomes for patients with mantle cell lymphoma have not changed appreciably since the mid-1990s, according to US registry data.[21]

It is interesting, however, that the impact of DIT/HDT has been verified outside of clinical trials. A Scandinavian study of more than 1,300 patients confirmed the positive impact of both rituximab-containing regimens and ASCT consolidation on OS in mantle cell lymphoma patients.[2] In the United States, data from the Surveillance, Epidemiology, and End Results (SEER) database comparing R-CHOP vs R-hyper-CVAD or R-CHOP/R-hyper-CVAD/ASCT confirmed, as we did in our series,[22] that outcomes of treatment with R-CHOP are clearly inferior to those of DIT/HDT strategies, both in terms of PFS and OS when comparing pooled data from patients treated with DIT/HDT vs R-CHOP alone.

Unfortunately, despite the availability of DIT/HDT strategies, a significant number of patients relapse over time and then experience only transient benefit from additional chemotherapy. Several novel therapies have been approved by the US Food and Drug Administration over the last 10 years for patients with mantle cell lymphoma: bortezomib (in December 2006), lenalidomide (in June 2013), and ibrutinib (in November 2013); also, temsirolimus was approved in August 2009 in the European Union. These new biologic agents have produced durable responses even in chemotherapy-refractory patients. Recently reported promising results of biologic combinations in the frontline setting using lenalidomide plus rituximab (38 patients)[23] or ibrutinib plus rituximab (50 patients)[24] raise the possibility of future nonchemotherapy options in mantle cell lymphoma. However, the follow-up of these studies is rather short and we do not yet have any experience regarding patients’ response to salvage therapy in these settings. Mantle cell lymphoma is a disease that frequently becomes chemoresistant over time, including after the use of biologic agents, as shown by a median OS of only 2.9 months following cessation of ibrutinib in one study,[25] justifying a degree of caution in moving forward.

Given their rather mild toxicity profile overall, the logical next step is to combine these biologic agents with current standard regimens used in mantle cell lymphoma. This approach has been applied successfully in elderly patients, for example, in treatment with R-CHOP plus bortezomib (leading to a new frontline standard).[10] Investigation of additional combinations with BR, such as with bortezomib, lenalidomide, or ibrutinib, is underway. Similar strategies should be applied in younger patients to build on the success of DIT/HDT, in order to deepen the initial response to treatment (ie, to achieve MRD-negative status) and thereby further reduce the risk of relapse, and through maintenance/consolidation strategies. The role of maintenance therapy in mantle cell lymphoma is growing, including its use post HDT,[7,26] and this approach might even help to improve OS (with longer follow-up) in patients under 65 years of age, as it did in the elderly patient setting.

In summary, use of DIT/HDT in conjunction with cytarabine-containing chemoimmunotherapy induction translates into long-term clinical benefit in mantle cell lymphoma, with an initial duration of response well beyond 7 to 8 years.[27] Ongoing studies looking at combinations with biologic agents might help to further improve mantle cell lymphoma outcomes, including in patients with high MIPI scores, as well as in refined patient subsets identified by biologic prognostic markers (Ki-67/MIPI-b),[15] p53 (17p deletion/mutation),[28] or even microRNAs.[29]

The landscape of mantle cell lymphoma is clearly evolving, due to the availability of new treatment options incorporating novel biologic agents. To optimize therapy, we should build on what has been accomplished over the last 3 decades-particularly through the use of DIT/HDT, which generated unprecedented rates of CR and molecular CR accompanied by very long durations of first remission. This implies that oncologists should continue to encourage clinical trials, implement MRD-based treatment decisions, and take into account the biologic diversity of the disease-and not just the patient’s age at diagnosis-with the goal of advancing “real-world” benefits for our patients with mantle cell lymphoma.

The author has no significant interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article

 Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27:511-8.

 Abrahamsson A, Albertsson-Lindblad A, Brown PN, et al. Real world data on primary treatment for mantle cell lymphoma: a Nordic Lymphoma Group observational study. Blood. 2014;124:1288-95.

 Skarbnik AP, Goy AH. Mantle cell lymphoma: state of the art. Clin Adv Hematol Oncol. 2015;13:44-55.

 Campo E, Rule S. Mantle cell lymphoma: evolving management strategies. Blood. 2015;125:48-55.

 Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005;23:1984-92.

 Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008;112:2687-93.

 Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2015;388:565-75..

 Robak T, Huang H, Jin J, et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015;372:944-53.

 Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381:1203-10.

 Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123:2944-52.

 Chen R, Li H, Bernstein S, et al. Pre-transplant R-bendamustine induces high rates of minimal residual disease in MCL patients: updated results of S1106: US Intergroup study of a randomized phase II trial of R-HCVAD vs. R-bendamustine followed by autologous stem cell transplants for patients with mantle cell lymphoma. Blood. 2015;126:abstr 518.

 Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the Second Nordic Mantle Cell Lyjmphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016;175:410-8.

 Chihara D, Cheah CY, Westin JR, et al. Rituximab plus hyper-CVAD alternating with MTX/Ara-C in patients with newly diagnosed mantle cell lymphoma: 15-year follow-up of a phase II study from the MD Anderson Cancer Center. Br J Haematol. 2016;172:80-8.

 Till BG, Gooley TA, Crawford N, et al. Effect of remission status and induction chemotherapy regimen on outcome of autologous stem cell transplantation for mantle cell lymphoma. Leuk Lymphoma. 2008;49:1062-73.

 Dahi PB, Tamari R, Devlin SM, et al. Favorable outcomes in elderly patients undergoing high-dose therapy and autologous stem cell transplantation for non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2014;20:2004-9.

 Chandran R, Gardiner SK, Simon M, Spurgeon SE. Survival trends in mantle cell lymphoma in the United States over 16 years 1992-2007. Leuk Lymphoma. 2012;53:1488-93.

 Mato AR, Svoboda J, Feldman T, et al. Post-treatment (not interim) positron emission tomography-computed tomography scan status is highly predictive of outcome in mantle cell lymphoma patients treated with R-HyperCVAD. Cancer. 2012;118:3565-70.

 Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373:1835-44.

 Wang ML, Lee H, Chuang H, et al. Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. Lancet Oncol. 2016;17:48-56.

 Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016;127:1559-63.

 Callanan M, Delfau M, Macintyre E, et al. Predictive power of early, sequential MRD monitoring in peripheral blood and bone marrow in patients with mantle cell lymphoma following autologous stem cell transplantation with or without rituximab maintenance; interim results from the LyMa-MRD project, conducted on behalf of the Lysa Group. Blood. 2015;126:abstr 497.

 Delfau-Larue MH, Klapper W, Berger F, et al. High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood. 2015;126:604-11.

 Husby S, Ralfkiaer U, Garde C, et al. miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator. Blood. 2015;125:2669-77.

The landscape of mantle cell lymphoma is clearly evolving, due to the availability of new treatment options incorporating novel biologic agents. To optimize therapy, we should build on what has been accomplished over the last 3 decades.

Oncology Vol 30 No 12

Amitkumar Mehta on the Immunomodulating Effects of Targeted Therapy for Multiple Myeloma

New Does Not Always Mean Better: Isolated Limb Perfusion Still Has a Role in the Management of In-Transit Melanoma Metastases

Breast Cancer After Hodgkin Lymphoma: The Price of Success

COUNTERPOINT: The Role of Stem Cell Transplantation in Mantle Cell Lymphoma

POINT: The Role of Stem Cell Transplantation in Mantle Cell Lymphoma