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Blood Podcast
The decline of transplant for relapsed myeloma; DDAVP response in bleeding disorders; dual DOT1L/EZH2 targeting in DLBCL
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Welcome to the April 17, 2025 episode of Blood Podcast, your source for innovative ideas and cutting edge information. Our topics are based on articles published in Blood A Journal of the American Society of Hematology. First on today's podcast the role of autologous transplant for relapsed myeloma in an updated analysis of the GMMG relapse trial, salvage autologous transplant offered no survival benefit compared to control chemotherapy. These findings may have clinical implications in an era of alternative and highly effective treatment options after that respond to DDAVP or desmopressin in bleeding disorders. This study is the first large scale meta analysis to assess the response rate to DDAVP and bleeding disorders. Authors provide new insights into determinants of response, which vary according to the disease type. Finally, turning to diffuse large B cell lymphoma Germinal center B cells depend on the activity of dot1 and ezh2 to maintain their pro proliferative identity. New research shows that combined treatment with DOT1, L&EZH2 inhibitors has synergistic activity in vitro. First, let's review the article on autologous transplant in relapsed multiple myeloma. This is long term follow up of the Phase 3 GMMG relapse trial. Marc Andrea Bartsch, the first author, is affiliated with the GMMG study group and the Heidelberg Myeloma center in Germany. The trial update addresses a critical what's the role of salvage transplant in the era of novel agents and immune therapies? There's an ongoing debate over optimal management of relapsed or refractory myeloma in patients who have previously received frontline high dose chemotherapy and autologous stem cell transplantation. Most guidelines recommend considering salvage transplant, especially in patients with a long time to progression since frontline transplant or TTP1. But there's one more factor to the emergence of highly effective non transplant treatment options, including triplet regimens and CAR T cell therapies. Unfortunately, there are few rigorous studies directly comparing novel treatments to salvage transplant. We do have some insights from a prospective randomized phase 3 study, the NCRI Myeloma X Relapse Intensive Trial. In this study, salvage transplant had superior pfs and os. The bad news is that the therapy used in the control group was suboptimal, a weekly cyclophosphamide regimen that is now outdated. But there is one other trial, GMMG relapse, the subject of this report. This study compares salvage transplant to a relevant novel therapy, Len lenalidomide, the immunomodulatory agent and Dex dexamethasone. The initial results of this study, previously published, were not favorable for the transplant arm. In the primary analysis, salvage transplant provided no survival benefit over Len Dex. However, there was an issue with the study. Nearly 29% of the patients in the transplant arm dropped out before actually undergoing the salvage procedure. In patients who did undergo salvage transplantation, results of landmark analyses suggested that survival was improved over lendex. Ultimately, though, the survival data were immature at the time, so researchers continued to follow the patients and now Birch and co authors are reporting a long term follow up analysis of the GMMG relapse trial with a median follow up of more than eight years. Before the results, let's step back and look at the trial design. The study included 282 adult patients with relapsed or refractory multiple myeloma, 94% of whom had received a frontline transplant. Patients were randomized to a salvage transplant arm or a control arm of continuous LEND X. Of note, the salvage also incorporated lendex. It was given as RE induction prior to high dose chemotherapy and autologous transplantation and again afterwards as maintenance therapy. Now onto the survival results. With a median follow up of 99 months, researchers found no significant difference in PFS at 20.5 months in the transplant arm and 19.3 months in the control arm. That translated into a hazard ratio of 0.98. Likewise, there was no significant difference in OS. The median OS was 67.1 months for transplant and 62.7 months for controls with a hazard ratio of 0.89 and a P value of 0.4. Due to that high dropout rate of 29% prior to salvage therapy, researchers conducted landmark analyses from around the time of salvage transplant. But these analyses didn't uncover any significant differences in PFS or OS. And finally, a valid question is whether a long TTP1 would predict survival benefit. Remember that TTP1 is time to progression after frontline transplant. TTP1 was a prognostic factor, but it did not predict benefit from salvage transplant from the subset of patients with a TTP one of 48 months or longer. The HR for PFS was 1.0 and the P value 0.99. So what can we take away from these findings? In a commentary, author Aurora Perrault describes it as the decline of transplant for relapsed myeloma. That's the title of the commentary by Perrault, who is with the University of Toulouse in Nantes, France. Perrault says that with no significant PFS or OS benefit compared to lendex. This study challenges our prior assumptions regarding the benefits of a salvage transplantation in patients with relapsed or refractory multiple myeloma. This study does have some limitations. There was substantial use of salvage transplantation in the control arm, which complicates the interpretation of survival outcomes. And the use of LENDEX doublet prior to salvage transplant is likely not optimal given recent data demonstrating that more active triplet regimens significantly improve outcomes. Nevertheless, these findings have important implications for for clinical practice. Perot says it's remarkable that even patients with TTP1 longer than 48 months did not have a significant survival advantage. That calls into question the current recommendations to use salvage transplant in this subgroup. And the lack of survival benefit raises questions about the routine use of salvage transplantation, especially when highly effective alternatives including triplets and CAR T cell therapies are an option. There may still be a role for salvage transplant in specific situations, such as resource limited settings or in patients who would prefer a fixed duration therapy. However, Perrault writes, the quality of life burden associated with transplant should be carefully weighed against the availability of less toxic alternatives. Next, let's turn to an article on DDAVP or desmopressin in bleeding disorders. What are the response rates and what are the determinants of response? This systematic review and meta analysis is by Sebastian Lan of Erasmus University Medical center in the Netherlands and co authors on behalf of the Symphony Consortium. Their study is the first large scale meta analysis to assess the response rate to DDAVP in different bleeding disorders. It's an important work given that DDAVP is one of the cheapest and most readily available treatments for patients with bleeding disorders. Yet the DDAVP response varies widely from patient to patient and the determinants of response remain unclear. DDAVP is a synthetic vasopressin analog. It's used to prevent or stop bleeding in patients with vwd, Von Willebrand disease or ha, among other conditions. Treatment with DDAVP increases endogenous levels of von Willebrand factor and factor VIII by three to five times their baseline values. The activity of DDAVP depends on availability, secretion and clearance of these blood glycoproteins. As a result, DDAVP is most often prescribed in patients not completely deficient in von Willebrand factor and factor VIII, such as patients with VWD type 1 and HA that's mild or moderate in severity. One of the biggest challenges in prescribing DDAVP is the substantial intra patient variability of response when DDAVP is prescribed, it's necessary to investigate how well a patient will respond. This involves a DDAVP test dose with multiple blood drawings. Patients who don't respond will require alternative treatments that are more expensive and likely to require hospital visits. To help streamline treatment decisions, it would be helpful to identify factors that influence individual patient response to ddavp. A number of studies have identified factors that influence response such as age, blood group type, disease severity, and mutation type. However, most of these studies are small and patient characteristics varied widely. In the current work, authors sought to systematically review medical literature for two purposes. First, to determine the response rate to DDAVP in different diseases, and second, to identify possible patient determinants that influence response to ddavp. The hope was that this would help provide a better understanding of the reasons behind non response. Their systematic review and meta analysis included studies of patients with any bleeding disorder receiving ddavp. The primary outcome was the proportion of patients with response to DDAVP. This was defined as factor level greater than 50 microliters per deciliter for complete response and 30-50 microliters per deciliter for partial response. Out of 591 articles identified, 103 were included. Of those, 71 articles encompassing 1,772 patients were suitable for the study's definition of response. The majority of the studies reported on DDAVP administered intravenously subcutaneously, or both. Only one study reported an intranasal administration. The average patient age was approximately 34 years and about 75% were male. The most common conditions were HA in 906 patients and VWD type 1 in 669 patients. The authors found that subtype of disease is a strong determinant of response. Their meta analysis showed a pooled response proportion of 0.71 for all patients and a significant difference in DDAVP response between disease subtypes. The overall proportion of complete response was 0.89 for VWD type 1, 0.83 in type 2, and 0.10 in type 3 for HA. The pooled response proportions were 0.90 for HA carriers, 0.54 for those with mild disease, 0.45 for studies of mild or moderate disease, and 0.16 for moderate only. Moving on to determinants of response for ha, higher baseline levels of factor VIII coagulant activity or factor VIII C was a borderline significant determinant of response end in VWD type 1. VWF antigen, VWF activity, and factor VIII C were all significant determinants of an increased response rate, age and weight may play a role in response for both HA and vwd. There were trends demonstrating correlations between higher age and response and higher weight and response. Finally, authors compared mutations in the factor VIII and VWF genes with response profiles. They found that responses to DDAVP were heterogeneous even for patients carrying the same MUT mutation. Altogether, authors say these differences in DDAVP response emphasize the need for a standardized response definition and further research into response mechanisms. This information can be used as a guide by clinicians treating patients with bleeding disorders. The analysis indicates that the vast majority of patients with VWD type 1 have a near complete DDAVP response, which supports the current guidelines regarding DDAVP testing in patients with VWD Type 1. Furthermore, the relatively low frequency of response in mild and mild moderate HA indicates that DDAVP response should be tested in those patients to ensure a sufficient response. However, despite the strong relationship between DDAVP response with baseline factor levels and disease subtype, individual DDAVP tests may still be required in these heterogeneous bleeding disorders. Finally, on today's podcast, a two pronged strategy in DLBCL diffuse large B cell lymphoma. The work is from Camille Goebel of the Netherlands Cancer Institute in Amsterdam and co authors. They report on combined targeting of dot1L and ezh2 in GCB DLBCL, the germinal center B cell subtype of the disease. By inhibiting dot1L and EZH2 simultaneously, the researchers have worked out an effective differentiation based control in these preclinical studies. Their work has important implications for dlbcl, a common lymphoid malignancy in need of new treatment options. The standard of care in DLBCL is R CHOP chemoimmunotherapy. This is a highly effective frontline Strategy, but approximately 40% of patients are refractory to treatment or experience relapse, and up to 14% of patients have MYC translocated DLBCL. This is an aggressive subtype with a poor prognosis, further highlighting the need for new therapies. To understand the promising new approach uncovered by Goebel et al, it's helpful to know more about the key players in their combination strategy. Differentiation of B cells into germinal center B cells depends on the activity of the transcription Factors MyC and BCl6. This process is also supported by two histone methyltransferases EZH2 and dot1L. EZH2 is the catalytic component of the polycomb repressive complex II or PRC2. GCB cells are pro proliferative. They rely on EZH2 to establish that pro proliferative identity and to maintain it Gain of function mutations in EZH2 promote malignant transformation, support cell survival and repress differentiation. Dot1L is also important in the pro proliferative phenotype. This epigenetic writer is required in the development of GCB cells and is essential for humoral immune responses. Previous attempts to target EZH2 or DOT1L individually have success. In a phase 2 trial of tazmatostat, an EZH2 inhibitor, the objective response rate was 35% in patients with EZH2 wild type follicular lymphoma and 69% in follicular lymphoma with EZH2 gain of function mutations turning to DOT1L in the mouse B cell lineage, loss of the DOT1L gene prohibits the formation of germinal cells, but in a phase one trial a dot1L inhibitor known as pinometastat had only modest clinical activity in adult acute leuke. The current work advances the field by elucidating the roles of dot1L and ezh2, specifically in the pathophysiology of GCB DLBCL and their results, as published in blood, show how GCB DLBCLs synergistically depend on the combined activity of dot1L and EZH2. Inhibiting both enzymes enhanced DE repression of PRC2 target genes compared to inhibiting EZH2 alone. The dual targeting approach also upregulated BCL6 target genes and suppressed MYC target genes. Together, these alterations resulted in what authors call a cell identity crisis. The GCB DLBCLs lose their pro proliferative GC identity and they partially undergo plasma cell differentiation, a process associated with poor survival. In vitro treatment with the combination of Dot1L and EZH2 inhibitors resulted in synergistic activity linked to loss of proliferation and subsequently plasma cell differentiation in GCB DLBCL cell lines. The dot1L EZH2 inhibition strategy produced significant toxicity in the majority of cases 7 out of 9 cell lines. Next, the researchers explored this dual EPI drugging strategy in vivo using a xenograft murine model. The combination of an EZH2 and DOT1L inhibitor prevented tumor growth, while treatment with either inhibitor alone was less effective than the combination in these mice. Body weight remained stable, though some nephrotoxicity and reduced erythropoiesis was observed, but there was no significant toxicity to the GI tract, heart, brain, lungs or liver Based on these results, authors concluded that dot1L and ezh2 cooperatively repress PRC2 target genes that are essential to maintain the pro proliferative GCB cell identity of dlbcl and by co targeting these enzymes they could induce GCB DLBCL to differentiate towards a plasma cell like state that is quote, incompatible with cell survival. As such, combined targeting of these epigenetic writers may be a promising foundation for an alternative treatment approach in dlbcl. Also of interest is a commentary authored by Jerome Moreau of the Academic Institute of France located in the city of Montpellier. The title is dual targeting of EZH2 and dot1L in DLBCL. In it, Moreau says the current work reveals the previously unrecognized therapeutic potentials of EZH2 and Dot1L inhibitors, given in combination as a differentiation based therapeutic strategy in GCB dlbcl. Of interest, he adds, the findings underline the existence of a mechanism involving dot1L in the silencing of PRC2 target genesis in GCB DLBCL cells independently of EZH2. Since both EZH2 and dot1L inhibitors have been clinically tested, Moreau concludes this new work should prompt clinical evaluation of the synergistic potential of this combination. You have been listening to the Blood Podcast. The articles mentioned in this podcast can be found@bloodjournal.org and are linked in the show notes of this episode. Be sure to join us next week for another episode. Thank you for listening.