Precision medicine for multiple myeloma: The case for translocation (11;14).

The t(11;14) translocation is among the most prevalent cytogenetic abnormalities in multiple myeloma (MM), distinguished by its unique features and biology that have been thoroughly explored for decades. What further sets this MM subtype apart is its oscillating prognostic significance, from initially being considered a favorable alteration to intermediate risk and potential future reclassification as favorable risk. Despite not being inherently a high-risk alteration indicative of an aggressive phenotype, it appears that t(11;14)-MM is less responsive to novel agents like proteasome inhibitors and immunomodulatory drugs which have otherwise transformed the disease's treatment landscape, perhaps partially explained by its reduced propensity for immunoglobulin production and oligosecretory nature. However, its distinct reliance on Bcl-2 has heightened its sensitivity to venetoclax. Further subclassification based on morphological and genomic characteristics could enhance our prediction models of treatment responses and enable more tailored therapeutic strategies for patients. This review aims to encapsulate the existing research evidence in this area.

Isocitrate dehydrogenase (IDH) 1 and 2 mutations predict better outcome in patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation: a study of the ALWP of the EBMT.

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations have uncertain prognostic implications in AML. We investigate the impact IDH1 and IDH2 mutations in AML patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1). In total, 1515 adult patients were included, 15.91% (n = 241) carried IDH1 mutation (mIDH1), and 26.27% (n = 398) IDH2 mutation (mIDH2) and 57.82% (n = 876) had no-IDH mutation. NPM1 was frequently encountered with IDH1 mutation (no-IDH group, n = 217, 24.8%, mIDH1, n = 103, 42.7%, mIDH2, n = 111, 27.9%, p < 0.0001). At day 180, the cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was significantly lower in mIDH1 and mIDH2 compared to no-IDH groups (Hazard ratio [HR] = 0.66 (95% CI 0.47-0.91), p = 0.011; HR = 0.73 (95% CI 0.56-0.96), p = 0.025, respectively). In the mIDH1 group, overall survival (OS) was improved compared to no-IDH (HR = 0.68 (95% CI 0.48-0.94), p = 0.021), whereas mIDH2 was associated with lower incidence of relapse (HR = 0.49 (95% CI 0.34-0.7), p < 0.001), improved leukemia free survival (LFS) (HR = 0.7 (95% CI 0.55-0.9), p = 0.004) and OS (HR = 0.74 (95% CI 0.56-0.97), p = 0.027). In the subgroup of NPM1 wild type, only IDH2 was associated with improved outcomes. In conclusion, our data suggest that IDH1 and IDH2 mutations are associated with improved outcomes in patients with AML undergoing allo-HCT in CR1.

Posttransplant cyclophosphamide versus anti-thymocyte globulin versus combination for graft-versus-host disease prevention in haploidentical transplantation for adult acute myeloid leukemia: A report from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party.

BACKGROUND: The optimal choice for graft-versus-host disease (GVHD) prophylaxis in haploidentical stem cell transplantation (haplo-SCT) remains debatable. Posttransplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are two common strategies, but little is known about their combination. METHODS: Using the European Society for Blood and Marrow Transplantation (EBMT) registry, the authors identified 3649 adult patients with acute myeloid leukemia (AML) who underwent haplo-SCT in complete remission between 2007 and 2021 at 260 EBMT-participating centers who received either PTCy (n = 2999), ATG (n = 358), or combination prophylaxis (n = 292). Cord blood transplants, combined bone marrow and peripheral grafts, and transplants with ex vivo graft manipulation were excluded. Median follow-up was 31.8 months. RESULTS: On multivariate analysis, adjusting for patient age and performance status, disease status at transplant, cytogenetic risk, conditioning intensity, stem cell source, female-to-male graft, and donor and patient CMV status, we present the following. Compared to PTCy, ATG had a higher risk of nonrelapse mortality (hazard ratio [HR], 1.6; p = .003), worse leukemia-free survival (HR, 1.4; p = .002), overall survival (HR, 1.49; p = .0009), and GVHD-free and relapse-free survival (HR, 1.29; p = .012). The combination of PTCy and ATG, however, led to significantly reduced rates of grade 2-4 (HR, 0.51; p = .0003) and grade 3-4 (HR, 0.5; p = .018) acute GVHD and did not affect any transplant outcomes compared to PTCy without ATG. CONCLUSION: The authors conclude that ATG alone is a less effective prophylaxis strategy compared to PTCy, however, the combination of PTCy and ATG is superior to either monotherapy. They propose that this combination could be considered a potential new standard of care for GVHD prophylaxis in haplo-SCT for AML.

Outcome of Stem Cell Transplantation in HTLV-1-Associated North American Adult T-Cell Leukemia/Lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) remains challenging to treat and has dismal outcome. Allogeneic stem-cell transplantation (allo-SCT) has promising results, but data remain scarce. In this single-center retrospective analysis of 100 patients with ATLL from north America (67 acute, 22 lymphomatous), 17 underwent allo-SCT and 5 autologous SCT (ASCT), with a median follow-up of 65 months. Post-transplant 3-years relapse incidence (RI) and non-relapse mortality (NRM) were 51% and 37%, respectively, and 3-year progression-free survival (PFS) and overall survival (OS) were 31% and 35%, respectively. ASCT 1-year RI was 80% compared to 30% in allo-SCT (p = 0.03). After adjusting for immortal-time bias, allo-SCT had significantly improved OS (HR = 0.4, p = 0.01). In exploratory multivariate analysis, patients achieving first complete response and Karnofsky score ≥ 90 had significantly better outcomes, as did Black patients, compared to Hispanics, who had worse outcome. In transplanted patients, 14 died within 2 years, 4 of which ASCT recipients. Our data are the largest ATLL transplant cohort presented to date outside of Japan and Europe. We show that allo-SCT, but not ASCT, is a valid option in select ATLL patients, and can induce long term survival, with 40% of patients alive after more than 5 years.

High-dose melphalan treatment significantly increases mutational burden at relapse in multiple myeloma.

High-dose melphalan (HDM) improves progression-free survival in multiple myeloma (MM), yet melphalan is a DNA-damaging alkylating agent; therefore, we assessed its mutational effect on surviving myeloma cells by analyzing paired MM samples collected at diagnosis and relapse in the IFM 2009 study. We performed deep whole-genome sequencing on samples from 68 patients, 43 of whom were treated with RVD (lenalidomide, bortezomib, and dexamethasone) and 25 with RVD + HDM. Although the number of mutations was similar at diagnosis in both groups (7137 vs 7230; P = .67), the HDM group had significantly more mutations at relapse (9242 vs 13 383, P = .005). No change in the frequency of copy number alterations or structural variants was observed. The newly acquired mutations were typically associated with DNA damage and double-stranded breaks and were predominantly on the transcribed strand. A machine learning model, using this unique pattern, predicted patients who would receive HDM with high sensitivity, specificity, and positive prediction value. Clonal evolution analysis showed that all patients treated with HDM had clonal selection, whereas a static progression was observed with RVD. A significantly higher percentage of mutations were subclonal in the HDM cohort. Intriguingly, patients treated with HDM who achieved complete remission (CR) had significantly more mutations at relapse yet had similar survival rates as those treated with RVD who achieved CR. This similarity could have been due to HDM relapse samples having significantly more neoantigens. Overall, our study identifies increased genomic changes associated with HDM and provides rationale to further understand clonal complexity.

Induction therapy prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma: an update.

The current standard of care model for newly diagnosed fit multiple myeloma (NDMM) patients is the sequential treatment of induction, high dose melphalan, autologous stem cell transplantation (ASCT), and maintenance. Adequate induction is required to achieve good disease control and induce deep response rates while minimizing toxicity as a bridge to transplant. Doublet induction regimens have greatly fallen out of favor, with current international guidelines favoring triplet or quadruplet induction regimens built around the backbone of the proteasome inhibitor bortezomib and dexamethasone (Vd). In fact, the updated 2021 European Haematology Association (EHA) and European Society for Medical Oncology (ESMO) clinical practice guidelines recommend the use of either lenalidomide-Vd (VRd), or daratumumab-thalidomide-Vd (Dara-VTd) as first-line options for transplant-eligible NDMM patients, and when not available, thalidomide-Vd (VTd) or cyclophosphamide-Vd (VCd) as acceptable alternatives. Quadruplet regimens featuring anti-CD38 monoclonal antibodies are extremely promising and remain heavily investigated, as is the incorporation of more recent proteasome inhibitors such as carfilzomib. This review will focus on induction therapies prior to ASCT examining the latest data and guidelines on triplet and quadruplet regimens.

IgM-MM is predominantly a pre-germinal center disorder and has a distinct genomic and transcriptomic signature from WM.

Immunoglobulin M (IgM) multiple myeloma (MM) is a rare disease subgroup. Its differentiation from other IgM-producing gammopathies such as Waldenström macroglobulinemia (WM) has not been well characterized but is essential for proper risk assessment and treatment. In this study, we investigated genomic and transcriptomic characteristics of IgM-MM samples using whole-genome and transcriptome sequencing to identify differentiating characteristics from non-IgM-MM and WM. Our results suggest that IgM-MM shares most of its defining structural variants and gene-expression profiling with MM, but has some key characteristics, including t(11;14) translocation, chromosome 6 and 13 deletion as well as distinct molecular and transcription-factor signatures. Furthermore, IgM-MM translocations were predominantly characterized by VHDHJH recombination-induced breakpoints, as opposed to the usual class-switching region breakpoints; coupled with its lack of class switching, these data favor a pre-germinal center origin. Finally, we found elevated expression of clinically relevant targets, including CD20 and Bruton tyrosine kinase, as well as high BCL2/BCL2L1 ratio in IgM-MM, providing potential for targeted therapeutics.

Predictive Factors for Outcome of First Allogeneic Transplant for Elderly Patients With Acute Lymphoblastic Leukemia.

INTRODUCTION/BACKGROUND: The treatment of acute lymphoblastic leukemia (ALL) in patients older than 70 is extremely challenging with dismal outcome. Allogeneic stem cell transplantation (alloHCT) has seen many advancements in the last decades showing benefits in younger ALL patients, but this treatment modality is decreasingly used with increasing age due to high treatment-related mortality. PATIENTS AND METHODS: We identified 84 ALL patients 70 to 84 years old allografted In 2002 to 2019 from a matched related (23%), unrelated (58%), haploidentical (17%), or cord blood (2%) donor at EBMT participating centers with a median follow-up of 23 months. RESULTS: The 2-year relapse incidence (RI) and non-relapse mortality were 37% and 28%, respectively, and 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were 35%, 39% and 23%, respectively. The strongest predictor of outcome was disease status at transplant whereby patients in first complete remission (CR1) had >50% 2-year OS, reflected in multivariate analysis (MVA) with significant improvement in RI, LFS, and GRFS (HR 0.23, 0.49, and 0.54, respectively). Furthermore, karnofsky score ≥90 reflective of good functional status positively influenced non-relapse mortality in both univariate and MVA (HR 0.37), and interestingly, donor CMV positivity appeared to negatively affect RI, LFS and OS in univariate analysis and RI in MVA (HR 2.87). CONCLUSION: Our data suggest that alloHCT is an option for elderly ALL patients, particularly those carefully selected and transplanted in CR1 especially if failed or without access to novel non-chemotherapy-based approaches.

Latest advances in the management of classical Hodgkin lymphoma: the era of novel therapies.

Hodgkin lymphoma is a highly curable disease. Although most patients achieve complete response following frontline therapy, key unmet clinical needs remain including relapsed/refractory disease, treatment-related morbidity, impaired quality of life and poor outcome in patients older than 60 years. The incorporation of novel therapies, including check point inhibitors and antibody-drug conjugates, into the frontline setting, sequential approaches, and further individualized treatment intensity may address these needs. We summarize the current treatment options for patients with classical Hodgkin lymphoma from frontline therapy to allogeneic hematopoietic stem cell transplantation and describe novel trials in the field.

Comprehensive Review of AL amyloidosis: some practical recommendations.

Amyloid light chain (AL) amyloidosis is among the more common and more severe of the amyloidoses usually involving the slow proliferation of a bone-marrow-residing plasma cell (PC) clone and the secretion of unstable immunoglobulin-free light chains (FLC) that infiltrate peripheral tissues and result in detrimental end-organ damage. Disease presentation is rather vague, and the hallmark of treatment is early diagnosis before irreversible end-organ damage. Once diagnosed, treatment decision is transplant-driven whereby ~20% of patients are eligible for autologous stem cell transplantation (ASCT) with or without bortezomib-based induction. In the setting of ASCT-ineligibility, bortezomib plays a central role in upfront treatment with the recent addition of daratumumab to the current emerging standard of care. In general, management of AL amyloidosis is aimed at achieving deep, durable responses with very close monitoring for early detection of relapse/refractory disease. This article provides a comprehensive review of the management of patients with AL amyloidosis including goals of therapy, current treatment guidelines in the setting of both ASCT-eligibility and ineligibility, treatment response monitoring recommendations, toxicity management, and treatment of relapse/refractory disease.

Allogeneic haematopoietic cell transplantation for myelofibrosis: a real-life perspective.

Myelofibrosis (MF) is a clonal stem cell neoplasm with heterogeneous clinical phenotypes and well-established molecular drivers. Allogeneic haematopoietic stem cell transplantation (HSCT) offers an important curative treatment option for primary MF and post-essential thrombocythaemia/polycythaemia vera MF or secondary MF. With a disease course that varies from indolent to highly progressive, we are now able to stratify risk of mortality through various tools including patient-related clinical characteristics as well as molecular genetic profile. Owing to the high risk of mortality and morbidity associated with HSCT for patients with myelofibrosis, it is important to improve patient selection for transplant. Our primary goal is to comprehensively define our understanding of current practices including the role of Janus Kinase (JAK) inhibitors, to present the data behind transplantation before and after leukaemic transformation, and to introduce novel personalization of MF treatment with a proposed clinical-molecular prognostic model to help elucidate a timepoint optimal for consideration of HSCT.

Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma.

BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.

Underdiagnosed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) as a major cause of multi-organ failure in acute leukemia transplant patients: an analysis from the EBMT Acute Leukemia Working Party.

Allogeneic hematopoietic cell transplantation (alloHCT) is a complex, potentially fatal therapy featuring a myriad of complications. Triggering event(s) of such complications vary significantly, but often a so-called "multi-organ failure" (MOF) is reported as the leading cause of death. The identification of the exact trigger of MOF is critical towards early and disease-specific intervention to improve outcome. We examined data from 202 alloHCT patients reported to have died of MOF from the EBMT registry aiming to determine their exact cause of death focusing on veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) due to its life-threatening, often difficult to capture yet preventable nature. We identified a total of 70 patients (35%) for whom VOD/SOS could be considered as trigger for MOF and leading cause of death, among which 48 (69%) were previously undiagnosed. Multivariate analysis highlighted history of hepatic comorbidity or gentuzumab use and disease status beyond CR1 as the only significant factors predictive of VOD/SOS incidence (OR = 6.6; p = 0.001 and OR = 3.3; p = 0.004 respectively). VOD/SOS-related MOF was widely under-reported, accounting for 27% of deaths attributed to MOF of unknown origin without a previous VOD/SOS diagnosis. Our results suggest most missed cases developed late VOD/SOS beyond 21 days post-alloHCT, highlighting the importance of the newly revised EBMT criteria.

Impact of Adding Antithymocyte Globulin to Posttransplantation Cyclophosphamide in Haploidentical Stem-Cell Transplantation.

BACKGROUND: Graft-versus-host disease (GVHD) is a major cause of mortality after allogeneic stem-cell transplantation. Posttransplantation cyclophosphamide (PT/CY) has become standard prophylaxis of GVHD in T-replete haploidentical transplantation. The question is whether adding antithymocyte globulin (ATG) to PT/CY may further reduce the incidence of GVHD compared to PT/CY only. PATIENTS AND METHODS: We retrospectively studied 268 patients undergoing myeloablative haploidentical transplantation with thiotepa, busulfan, and fludarabine (TBF) conditioning. Sixty-nine patients (26%) received ATG. RESULTS: In the ATG group, 3% died due to GVHD versus 8% in the no ATG group. The 100-day and 1-year nonrelapse mortality (NRM) was 0% and 19%, respectively, in the whole cohort. On univariate analysis, the 1-year NRM was 8% versus 23% in patients receiving ATG and no ATG, respectively (P = .005). The no ATG group had a higher incidence of acute GVHD at 12 months compared to the ATG group (22% vs. 12%, respectively, P = .029). The ATG group had better overall survival at 12 months compared to the no ATG group (79% vs. 69%, P = .029). On multivariate analysis, adding ATG to PT/CY had no significant impact on any of the outcomes. A low disease risk index was associated with better overall survival and lower NRM, while Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score ≥ 3 was associated with higher NRM. CONCLUSION: ATG can be safely used as part of the pretransplantation conditioning and does not increase the incidence of relapse or complications after transplantation.

Epstein-Barr virus-related post-transplant lymphoproliferative disease (EBV-PTLD) in the setting of allogeneic stem cell transplantation: a comprehensive review from pathogenesis to forthcoming treatment modalities.

Epstein-Barr virus (EBV) is a ubiquitous herpes virus that infects the majority of the population worldwide. The virus can establish a lifelong latent infection in host B-lymphocytes. In the setting of immunocompromise as is the case post transplantation, the virus can reactivate and cause one of the deadliest complications post hematopoietic stem cell transplantation (HSCT), post-lymphoproliferative disease (PTLD), the incidence of which has been increasing. Multiple risk factors have been associated with the onset of PTLD such as age, reduced intensity conditioning, EBV serology mismatch and cytomegalovirus (CMV) reactivation. The rarity of clinical trials involving PTLD and the lack of approved treatment modalities renders the management of PTLD challenging. While the first-line treatment involves weekly administration of rituximab, there is no consensus when treating rituximab-refractory PTLD. There is a handful of clinical trials that investigate the role of EBV-specific cytotoxic T-lymphocytes (CTLs) and novel agents, such as bortezomib, lenalidomide, everolimus, panobinostat, and brentuximab. This article aims to explore the entity of EBV-PTLD in HSCT recipients, expanding on clinical presentation, risk factors, modes of monitoring and treatment, and so highlighting the gaps in knowledge that are needed in order to build a treatment paradigm suitable for all patients at risk.

Allogeneic stem-cell transplantation with sequential conditioning in adult patients with refractory or relapsed acute lymphoblastic leukemia: a report from the EBMT Acute Leukemia Working Party.

Treatment of relapsed/refractory acute lymphoblastic leukemia (RR-ALL) remains a clinical challenge with generally dismal prognosis. Allogeneic stem-cell transplantation using sequential conditioning ("FLAMSA"-like) has shown promising results in relapsed/refractory acute myeloid leukemia, but little is known about its efficacy in RR-ALL. We identified 115 patients (19-66 years) with relapsed (74%) or primary-refractory (26%) ALL allografted from matched related (31%), matched unrelated (58%), or haploidentical donor (11%). Median follow-up was 37 (13-111) months. At day 100, cumulative incidences of grade II-IV/III-IV acute graft-versus-host-disease (GVHD) were 30% and 17%, respectively. Two-year cumulative incidence of chronic GVHD was 25% with 11% extensive cases. Two-year relapse incidence (RI) was 45%, non-relapse mortality was 41%. Two-year leukemia free survival (LFS) was 14%, overall survival (OS) 17%, and GVHD relapse-free survival (GRFS) was 14%. In multivariable analysis, Karnofsky score <90 negatively affected RI, LFS, OS, and GRFS. Conditioning with chemotherapy alone, compared with total body irradiation (TBI) negatively affected RI (HR = 3.3; p = 0.008), LFS (HR = 1.94; p = 0.03), and OS (HR = 2.0; p = 0.03). These patients still face extremely poor outcomes, highlighting the importance of incorporating novel therapies (e.g., BITE antibodies, inotuzumab, CAR-T cells). Nevertheless, patients with RR-T-cell ALL remain with an unmet treatment need, for which TBI-based sequential conditioning could be one of few available options.

Allogeneic transplant for FLT3-ITD mutated AML: a focus on FLT3 inhibitors before, during, and after transplant.

FMS-like tyrosine kinase 3 (FLT3) mutations are one of the most frequently encountered genetic alterations in acute myeloid leukemia (AML), and are generally associated with unfavorable outcomes. Several tools are currently available to provide an accurate prognosis for patients with these mutations, including FLT3 mutation type (internal tandem duplication versus tyrosine kinase domain), mutation allelic ratio (high versus low), and concurrent nucleophosmin-1 (NPM1) mutation, to help decide on optimal treatment. Recent advances in targeted therapies have paved the way for modern treatment strategies, such as the development of FLT3 kinase inhibitors. These novel drugs can be incorporated into any treatment component, including induction and consolidation, the relapse/refractory setting, bridging for transplant, salvage post-transplant, and as prophylactic long-term post-transplant maintenance. Many challenges remain though, such as their intolerability with high-dose chemotherapy in frail patients; whether their optimal use involves watchful waiting for molecular or hematologic relapse compared with prophylactic use as maintenance; and the exact role and indication for allogeneic stem cell transplantation, which arguably remains the only curative option for these high-risk patients.