Spotlight on Melphalan Flufenamide: An Up-and-Coming Therapy for the Treatment of Myeloma.

Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment. Melphalan (L-PAM) is an ageless drug. However, its use in the autologous stem cell transplantation (ASCT) setting and the innovative quadruplet regimen as well as daratumumab, bortezomib, and prednisone make this old drug current yet. Melflufen is a peptide-conjugated alkylator belonging to a novel class of compounds, representing an overcoming of L-PAM in terms of mechanism of action and effectiveness. The improved melflufen cytotoxicity is related to aminopeptidase activity, notably present in normal and neoplastic cells and remarkably heavily overexpressed in MM cells. Upon entering a cell, melflufen is cleaved by aminopeptidases, ultimately releasing the L-PAM payload and eliciting further the inflow and cleavage of the conjugated peptide. This virtuous loop persists until all extracellular melflufen has been utilized. The aminopeptidase-driven accumulation results in a 50-fold increase in L-PAM cell enrichment as compared with free alkylator. This condition produces selective cytotoxicity, increased on-target cell potency, and decreased off-target cell toxicity, ultimately overcoming resistance pathways triggered by previous treatments, including alkylators. Due to its distinct mechanism of action, melflufen plus dexamethasone as a doublet, and in combination with other novel drugs, has the potential to be beneficial for a broad range of patients with relapsed/refractory (RR) MM in third- or even in second-line therapy. The safety profile of melflufen has been consistent across studies, and no new safety concerns have been identified when melflufen was administered in doublet and triplet combinations. Based on growing clinical evidence, melflufen could be not only a good addition in the fight against RRMM but also a drug with a very favorable tolerability profile.

Clinical relevance of clonal hematopoiesis in persons aged ≥80 years.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes.

PURPOSE: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication. METHODS: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed. RESULTS: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (SF3B1, SRSF2, and U2AF1) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with SF3B1 mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within SF3B1- and SRSF2-related MDS. MDS with complex karyotype and/or TP53 gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of TP53 mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features. CONCLUSION: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.

TP53 dysfunction in chronic lymphocytic leukemia: clinical relevance in the era of B-cell receptors and BCL-2 inhibitors.

INTRODUCTION: Patients with TP53 dysfunction, assessed by del(17p) or TP53 mutations, respond poorly to chemo-immunotherapy and fare better with the new therapies (BCR and BCL-2 inhibitors); however, it is unclear whether their response is similar to that of patients without anomalies or whether there is currently an adequate determination of TP53 dysfunction. AREA COVERED: A literature search was undertaken on clinical trials and real-world experience data on patients with TP53 dysfunction treated with different protocols. Moreover, data on the TP53 biological function and on the tests currently employed for its assessment were reviewed. EXPERT OPINION: Although TP53 dysfunction has less negative influence on the new biological therapies, patients with these alterations, particularly those with biallelic inactivation of TP53, have a worst outcome with these therapies than those without alterations. At present, a determination of TP53, particularly with next generation sequencing (NGS) methodologies, may be sufficient for the identifications of the patients unsuitable for chemo-immunotherapy, although integration with del(17p) would be advisable. For the future, more extensive determinations of the TP53 status, including functional assays, may become part of the current armamentarium for a better patient stratification and treatment with newer protocols.

An in-depth evaluation of acalabrutinib for the treatment of mantle-cell lymphoma.

Introduction: Regimens involving intensive immuno-chemotherapy, followed by high-dose therapy and autologous stem cell transplant represent the standard treatment for younger fit patients with mantle cell lymphoma (MCL). Targeted approaches (i.e. ibrutinib, bortezomib, and lenalidomide) represent the backbone of therapy for relapsed cases.Areas covered: Acalabrutinib is a novel small molecule with a butynamide moiety specifically designed to irreversibly inhibit Bruton tyrosine kinase (BTK), which is more potent and selective than ibrutinib. Relevant publications have been identified through literature searches using the terms 'mantle cell lymphoma' and 'acalabrutinib'.Expert opinion: Acalabrutinib has been approved for the treatment of relapsed/refractory (RR) MCL patients. To date, clinical trials have reported some adverse effects such as cardiac toxicity or atrial fibrillation. Acalabrutinib in combination with other drugs, either in chemo-containing or chemo-free schedules, represent a valid option for MCL. However, none of the treatment schedules containing BTK inhibitors have been shown to be curative in MCL. Acalabrutinib may ultimately represent an option for patients who are 'fit' and exhibit well-controlled disease, which often characterizes only a limited 'niche' among MCL patients.

Pretransplant active disease status and HLA class II mismatching are associated with increased incidence and severity of cytokine release syndrome after haploidentical transplantation with posttransplant cyclophosphamide.

Cytokine release syndrome (CRS) represents a life-threatening side effect after haploidentical stem cell transplantation (Haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). Factors predictive of CRS development is still a matter of debate. We retrospectively analyzed 102 consecutive patients receiving a bone marrow (BM) (n = 42) or peripheral blood stem cells (PBSC) (n = 60) Haplo-SCT with PT-Cy. The two cohorts were similar in main patients' characteristics besides disease type (P = .02). Cumulative incidence of grades 1, 2, and ≥3 CRS was 80%, 52%, and 15% at a median of 2, 4, and 7 days, respectively. Moderate/High-grade fever (39°-41°), grade 1 and grade ≥3 CRS occurred more frequently after PBSC relative to BM grafts (68% vs 33%, P = .0005; 87% vs 71%, P = .009; 20% vs 7%, P = .07). Only patients experiencing grade ≥3 CRS had a worse outcome in terms of 1-year overall survival (OS) and nonrelapse mortality (NRM): 39% vs 80% (P = .002) and 40% vs 8% (P = .005), respectively. By univariate analysis the only factors associated with the increased risk of ≥3 CRS were pretransplant disease status (8% for complete remission, 11% for partial remission, and 38% for active disease, P = .002), HLA-DRB1 mismatching (57% vs 14%, P = .007), and PBSC graft (P = .07). By multivariable analysis, only pretransplant disease status (hazard ratio, HR: 6.84, P = .005) and HLA-DRB1 mismatching (HR: 17.19, P = .003) remained independent predictors of grade ≥3 CRS. Only grade ≥3 CRS is clinically relevant for the final outcome of patients receiving Haplo-SCT with PT-Cy, is more frequent after a PBSC graft and is associated with pretransplant active disease and HLA-DRB1 mismatching.

Lenalidomide for the treatment of mantle cell lymphoma.

INTRODUCTION: Although a variety of therapeutic schemes for Mantle Cell Lymphoma (MCL) have been attempted, the clinical outcome of patients continues to be unsatisfactory especially among patients with a very high-risk profile and in the relapsed/refractory setting. For this reason, recent clinical trials have explored novel approaches, either by the use of biological agents in chemotherapy-free schedules or by integrating them with chemoimmunotherapy regimens. Areas covered: The efficacy of lenalidomide monotherapy and combination therapy established in clinical studies mainly involving relapsed/refractory MCL is reviewed. The mechanism of action of lenalidomide is also discussed. Furthermore, the current position of lenalidomide in the MCL treatment algorithm is debated. Expert opinion: Lenalidomide demonstrated high efficacy and tolerability in several clinical trials as well as in retrospective real-world reports, even in patients who relapsed or were resistant to bortezomib and ibrutinib. In 2013, lenalidomide was approved by the Food and Drug Administration (FDA) for relapsed/refractory MCL after two prior therapies including at least one prior treatment with bortezomib. However, the potential synergistic anti-neoplastic effects of lenalidomide in combination with other biological agents, i.e. ibrutinib and venetoclax, especially in the management of p53-mutated cases, still remain an open issue.

A reduced dose of fluconazole as primary antifungal prophylaxis is not associated with increased risk of invasive fungal infections after allogeneic stem cell transplantation from a HLA identical sibling.

BACKGROUND: Invasive fungal infections (IFI) represent a common side effect of allogeneic hematopoietic stem cell transplant (allo-SCT), resulting in increased non relapse mortality (NRM) and reduced overall survival (OS) rates. Seventy-five days of Fluconazole 400 mg/d represents the standard primary antifungal prophylaxis (PAP) after allo-SCT, especially for low-risk transplants. However, the ideal dosage of fluconazole has never been tested. METHODS: Here, we report the experience of our institution on 113 consecutive patients receiving an allo-SCT from a HLA identical sibling between 1999 and 2015, where PAP consisted of fluconazole 100 mg/d only during the pre-engraftment phase. At the time of transplant, all patients were considered at low-risk for mold infection according to ECIL-5 guidelines. RESULTS: Cumulative incidence of possible-probable-proven IFI was 11.7%, while proven-probable (PP-IFI) occurred in 5.5% of patients by day 100 post transplant. Of note, only 1 patient developed invasive Candidiasis due to a non-albicans strain and stool-screening tests were negative for colonization by Candida albicans species. The incidence of 1-year acute and 2-year chronic graft-versus-host-disease (GVHD) was 30% and 45%, respectively. Three-year OS and 1-year NRM were 53% and 11.3%, respectively. CONCLUSION: In summary, fungal prophylaxis with fluconazole 100 mg/d results in very low incidence of PP-IFI, GVHD and NRM in low-risk allo-SCT.

Genomic Integration of HHV-6 Mimicking Viral Reactivation after Autologous Stem Cell Transplantation.

The monitoring of Human Herpesvirus 6 (HHV-6) after allogeneic stem cell transplantation has proven to be useful in preventing life-threatening complications; however, the pathogenic role of HHV-6 after autologous transplantation is not well-characterized, although viral reactivation might be responsible for significant complications even after this type of transplant. Here we report, for the first time to our knowledge, the case of a patient with chromosomally integrated HHV-6 (ciHHV-6), presenting with high titers of HHV-6 DNA copies after autologous transplantation, mimicking HHV-6 reactivation. The presence of viral DNA in the follicle bulb confirmed the ciHHV-6 and allowed for the discontinuation of the antiviral treatment. Due to the increasing awareness of HHV-6 potential pathogenicity and the fact that ciHHV-6 is expected in 1-2% of the population, such a case might be helpful in recognizing ci HHV-6, thus avoiding unnecessary and potentially toxic antiviral therapy once the viral genomic integration is confirmed.

T Cell-Replete Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for Hodgkin Lymphoma Relapsed after Autologous Transplantation: Reduced Incidence of Relapse and of Chronic Graft-versus-Host Disease Compared with HLA-Identical Related Donors.

Allogeneic hematopoietic stem cell transplantation (SCT) represents a potential curative strategy for patients with Hodgkin lymphoma (HL) relapsing after autologous SCT (ASCT), but the incidence of disease relapse is still high. We performed a retrospective study on 64 patients with HL relapsing after ASCT to compare outcomes after HLA-identical SCT (HLAid-SCT; n = 34) and haploidentical SCT with post-transplantation cyclophosphamide (PT-Cy) (Haplo-SCT; n = 30). All patients engrafted, with a significantly shorter median time for neutrophil and platelet engraftment after HLAid compared with Haplo-SCT (14 days versus 19 days and 11 days versus 23 days, respectively; P < .005). With a median follow-up of 47 months, 3-year overall survival (OS), 3 -year progression-free survival (PFS), and 1-year nonrelapse mortality (NRM) were 53%, 44% and 17%, respectively. Recipients of Haplo-SCT were less likely to experience disease relapse (3-year cumulative incidence of relapse, 13% versus 62%; P = .0001) and chronic graft- versus-host disease (GVHD; 3% versus 32%; P = .003), resulting in improved PFS (60% versus 29%; P = .04) and GVHD-free/relapse-free survival (47% versus 17%; P = .06). The 3-year OS did not differ between the 2 groups (56% versus 54%; P not significant), and NRM was higher after Haplo-SCT, but the difference did not reach statistical significance (26% versus 9%; P = .09). On multivariate Cox regression analysis, receipt of Haplo-SCT (hazard ratio [HR], .17; P = .02) and achieving optimal disease control (complete remission before SCT: HR, .6; P < .0001) were the only independent variables associated with a reduced risk of disease relapse. Haplo-SCT is a valid option for patients with HL relapsing after ASCT, with a reduced incidence of relapse compared with HLAid SCT.

Human Herpesvirus 6 replication predicts Cytomegalovirus reactivation after allogeneic stem cell transplantation from haploidentical donor.

BACKGROUND AND OBJECTIVES: Since HHV-6 reactivation after transplant has been reported to increase the risk of CMV infection, we tested this hypothesis in the HLA-haploidentical hematopoietic stem cell transplantation setting. STUDY DESIGN: From February 2011 to October 2015, 75 patients received hematopoietic stem cell transplantation using a T-cell replete graft from a HLA-haploidentical donor at our Institution. RESULTS: Interestingly, 87% of HHV-6 reactivations were followed by a CMV reactivation, at a median of 15days between the two viruses. Incidence of CMV reactivation was 14.5-fold higher in those patients with prior HHV-6 reactivation vs. those without it (p-value<0.001). CONCLUSION: The present results suggest that HHV-6 can be considered as a predicting indicator of cellular immunosuppression preceding the onset of CMV infection.

Donor lymphocyte infusion after allogeneic stem cell transplantation.

Allogeneic stem cell transplantation (allo-SCT) is considered the cornerstone in the treatment of several malignant and not malignant hematological diseases. However, relapse of hematological disease after allo-SCT is considered the most challenging point in the field. The risk can be reduced through optimal patients, donor and disease selection before allo-SCT, but harnessing donor immune system is an appealing way to treat or avoid disease relapse. Donor lymphocyte infusion (DLI) is a simple and effective therapy after allo-SCT. In this paper, the efficacy of DLI will be analyzed in different hematological diseases, focusing also on their therapeutic or pre-emptive use.

Desensitization with plasma exchange in a patient with human leukocyte antigen donor-specific antibodies before T-cell-replete haploidentical transplantation.

BACKGROUND: The presence of human leukocyte antigen donor-specific antibodies (DSAs) increases the risk of graft failure in T-cell-replete haploidentical hematopoietic stem cell transplantation (haplo-HSCT) CASE REPORT: A 49-year-old female with high-risk acute myeloid leukemia in first complete remission received a haplo-HSCT from her daughter. Pretransplant recipient screening examination showed high DSAs levels against unshared class I leukocyte antigens. RESULTS: The patient underwent a desensitization program consisting of plasma exchange (PEX), polyvalent intravenous (IV) immunoglobulins, and IV tacrolimus and mycophenolate mofetil (MMF). This protocol resulted in the disappearance of the DSA anti HLA B41. Engraftment was prompt with stable full donor chimerism. CONCLUSIONS: This case report suggests that the adopted scheme is safe for reducing DSA levels and facilitating donor engraftment in patients scheduled for haplo-HSCT.

Sorafenib for the treatment of multiple myeloma.

INTRODUCTION: Sorafenib is an orally available compound that acts predominantly by targeting the Ras/Raf/MEK/ERK pathway and by inhibiting the vascular endothelial growth factor (VEGF). Since the Ras/Raf/MEK/ERK pathway is implicated in the proliferation of multiple myeloma (MM) cells and VEGF in bone marrow neovascularization, sorafenib is a drug offering the potential for targeting two important pathogenetic mechanisms involved in MM. Thus, sorafenib is being proposed for use in MM. AREAS COVERED: In this review, the authors discuss the rationale for the use of sorafenib in MM. They then summarize the clinical development of sorafenib in MM, from initial Phase I to Phase II studies. A systematic literature review of the trials was performed using PubMed. EXPERT OPINION: Preliminary data from phase I/II trials showed that sorafenib had a good safety profile but minimal anti-myeloma activity as a single agent in relapsed/refractory patients. Results of phase II trials, evaluating sorafenib combined with new drugs, such as bortezomib and lenalidomide are eagerly awaited.

Ixazomib for the treatment of multiple myeloma.

INTRODUCTION: Proteasome inhibition is a mainstay in the treatment of multiple myeloma (MM). Bortezomib, the first proteasome inhibitor (PI) approved for MM therapy, has shown efficacy in relapsed/refractory patients and in the front-line setting. Among second-generation PIs, MLN9708 ( ixazomib ) is the first oral compound to be evaluated in MM treatment and has shown improvement in pharmacokinetic and pharmacodynamic parameters compared with bortezomib with a similar efficacy in the control of myeloma growth and in the prevention of bone loss. AREAS COVERED: In this review, the authors discuss the rationale for use of PIs. They then summarize the clinical development of ixazomib in MM, from initial Phase I to Phase II studies as a monotherapy and in combination with other chemotherapeutics. EXPERT OPINION: Preliminary data of Phase I/II trials showed that ixazomib had a good safety profile and exerted anti-myeloma activity as a single agent in relapsed/refractory patients. Furthermore, ixazomib also had efficacy in patients who were refractory to bortezomib. Its use in combination with lenalidomide and dexamethasone was shown to be an effective and well-tolerated regimen in up-front treatment leading to minimal residual disease negativity in a significant number of patients. Results of Phase III trials, evaluating ixazomib in induction or maintenance therapy, are awaited.

Bendamustine in multiple myeloma.

The advent of high-dose melphalan with autologous stem-cell transplantation (ASCT), the availability of novel agents such as thalidomide, lenalidomide (immunomodulatory drugs or IMiDs) and bortezomib (proteasome inhibitor) and improvements in supportive care have allowed to increase overall survival in multiple myeloma (MM) patients; nevertheless, MM remains an incurable pathology. For this reason, newer agents are required for continued disease control. Bendamustine is an old drug rediscovered in the last decade. In fact, its unique mechanism of action with structural similarities to both alkylating agents and antimetabolities, but which is not cross-resistant to alkylating agents, has reawakened interest in the use of this drug in the treatment of MM. Studies have proven the safety and efficacy of bendamustine administered alone or in combination with new drugs in both upfront and relapse/refractory settings of MM patients, including those with renal impairment. Moreover, bendamustine has been successfully used as conditioning for autologous stem-cell transplantation. Finally, the use of bendamustine does not compromise peripheral blood stem-cell collection. This drug is generally well tolerated, with the majority of adverse events being due to myelosuppression. Non-haematological adverse events are infrequent and usually mild.

Promising therapies for the treatment of chronic lymphocytic leukemia.

INTRODUCTION: The combination schedule of fludarabine, cyclophosphamide and rituximab is the gold standard of therapy for younger, physically fit chronic lymphocytic leukemia (CLL) patients; it allows achieving high and durable complete response rates. Although treatment outcome has considerably improved with chemo-immunotherapy, most patients eventually relapse and CLL is still incurable. Thus, newer and more rationally developed drugs are needed to improve CLL therapy, particularly in cases of relapsed/refractory disease. AREAS COVERED: The authors review preclinical and clinical data regarding newer CLL agents, currently undergoing examination, such as: signal transduction and cyclin-dependent kinase inhibitors, immunomodulatory agents, B-cell lymphoma 2 inhibitors, next generation mAbs, heat shock protein 90 and histone deacetylase inhibitors, and chimeric antigen receptor T-cell therapy. EXPERT OPINION: Newer compounds with different mechanisms of action, such as B-cell receptor signal transduction inhibitors, lenalidomide, next generation mAbs and several pro-apoptotic molecules, have shown efficacy in relapsed or refractory CLL patients. Several studies are under way to investigate the efficacy of combinations of these novel drugs. Hopefully, the combined use of these molecules in risk-adapted treatment strategies will change the therapeutic approach in the near future and will pave the way for a long-term control of CLL.