News of the Week

Key points:

• Diagnosis: The diagnosis of multiple myeloma (MM) requires ≥ 10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more MM defining events: CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥ 60%, serum involved/uninvolved free light chain (FLC) ratio ≥ 100 (provided involved FLC is ≥ 100 mg/L and urine monoclonal protein is ≥ 200 mg/24 h), or > 1 focal lesion on magnetic resonance imaging.
• Risk Stratification: High-risk MM is defined by the presence of del(17p), p53 mutation, or bi-allelic del(1p); t(4;14), t(14;16), t(14;20) in combination with gain(1q) or del(1p); or gain(1q) plus del(1p).
• Initial therapy: Consists of a quadruplet regimen consisting of anti-CD38 monoclonal antibody (daratumumab or isatuximab) plus bortezomib, lenalidomide, dexamethasone (VRd) followed by autologous stem cell transplantation in eligible patients.
• Selected standard-risk patients can delay transplant until first relapse.
• Frail patients who are not candidates for transplant are treated with a triplet regimen, either anti-CD 38 antibody plus lenalidomide and dexamethasone, or VRd.
• Maintenance Therapy: Standard maintenance is lenalidomide in combination with daratumumab or isatuximab. Lenalidomide is discontinued after 2 years in standard-risk patients. Bortezomib plus lenalidomide is an alternative option for high-risk MM.
• Management of relapsed disease: Major options are chimeric antigen receptor T-cell therapy, bispecific antibodies, various triplet regimens, and belantamab mafadotin.
• Management of Smoldering MM: Daratumumab for 3 years should be considered in high-risk smoldering MM.

Professors V. Rajkumar and S Kumar present their perspective on the inclusion of plasma cell leukemia (PCL) in the high-risk multiple myeloma (MM) category. Here are some key insights:

• PCL is an aggressive plasma cell malignancy characterised by the presence of a high percentage of circulating clonal plasma cells on conventional peripheral blood smear examination.
• Circulating plasma cells—the defining feature of PCL—are present in almost all patients with MM. Thus, the term PCL merely reflects the high end of a continuum, with the main difference being a quantitative arbitrary threshold based on the percentage of circulating plasma cells.
• One of the key drivers of their proposal is to make progress against this aggressive malignancy, and to include such patients in clinical trials for MM.
• The term plasma cell leukaemia creates substantial confusion and concern to patients, and it is time for a change.
• Finally, they provide counterarguments to their proposal and highlight the need to harmonise these proposed changes in disease definitions used by health organisations.

Key points:

• T-cell–engaging bispecific antibodies (BsAbs) have transformed the treatment landscape for multiple hematologic malignancies and are under investigation in the frontline setting, within combination regimens, and for nonmalignant
• Infections are frequent and represent the principal cause of nonrelapse mortality. These risks with repeated BsAb dosing arise from multifactorial mechanisms, including B-cell or plasma-cell aplasia, hypogammaglobulinemia, and early cytopenias.
• Additional contributors such as T-cell exhaustion, cytokine-directed immune modulation, and disease-related immunodeficiency, further compound infection risk. The result is a dynamic and cumulative impairment of host immunity that evolves over the course of therapy.
• Infectious disease screening before initiating BsAb therapy (See Table 1 in original paper):

1. Required

• Human immunodeficiency virus (HIV) using the fourth-generation antigen/antibody combination: HIV-1/2 immunoassay
• Hepatitis B virus (HBV) surface antigen, anti-HBV surface antibody, and anti-HBV core antibody
• Hepatitis C virus immunoglobulin G (IgG)

2. Considered

• Herpes simplex virus (HSV)-1 and HSV-2 IgG
• Varicella zoster virus IgG
• Cytomegalovirus IgG
• Toxoplasma gondii IgG
• Mycobacterium tuberculosis skin test and/or blood interferon gamma–release assay
• Strongyloides stercoralis IgG or empiric treatment
• Vaccination before initiation of BsAb therapy may be the optimal window to maximize immunogenicity, given the anticipated escalation in immune suppression with ongoing treatment. The authors recommend that patients receive indicated seasonal, annual, and age-appropriate nonlive vaccines at least 2 weeks before starting therapy, when feasible. This is particularly relevant because vaccine responses during active BsAb therapy may be substantially impaired (See Table 2 in original paper).
• See Figure 3 in original paper for immunoglobulin G replacement therapy (IGRT) strategies. The authors acknowledge that use of IGRT is logistically complex, can add financial strains, and access may be limited in some settings. Duration of IGRT will vary by clinical context, but a suggested approach is to continue for at least 6 months after the final BsAb cycle, or until serum IgG levels are >400 mg/dL, whichever is longer.
• Prophylactic: History of infections; multiple myeloma > non-Hodgkin lymphoma; severely low IgG <200 mg/dL; immunocompromised state (B-cell aplasia). Trigger: Initiation of therapy (or early in the course), regardless of IgG level or infection history.
• Pre-emptive: No infection history; expected IgG <400mg/dL; high inflammatory and tumor burden markers. Trigger: Declining IgG below a predefined threshold or early isolated or mild harbinger infections.
• Rescue: Young, no comorbidities; intact hematopoiesis; low inflammatory and tumor burden markers; IgG >600mg/dL. Trigger: Hospitalization for infection, recurrent infections (>1 bacterial infection), or prevent serious infection.

Key points:

• Recommendations:

1.  Initial therapy with a combination of rituximab plus corticosteroids or a thrombopoietic agent plus corticosteroids rather than corticosteroids alone (conditional recommendation).
2. A thrombopoietic agent (strong recommendation) or rituximab (conditional recommendation) for patients who failed first-line corticosteroids.
3. For adults with primary immune thrombocytopenia (ITP) needing additional treatment after initial therapy with corticosteroids (with or without IVIG), who are either ineligible for or choose not to receive a thrombopoietic agent or rituximab, the American Society of Hematology guideline panel suggests a Bruton’s tyrosine kinase (BTK) inhibitor, mycophenolate mofetil (MMF), or a spleen tyrosine kinase (SYK) inhibitor (conditional recommendation based on very low certainty in the evidence).

• Good practice statements:

1. If feasible, splenectomy should be delayed for at least one year after diagnosis because of the potential for remission.
2. Switching to a different thrombopoietic agent may be considered based on insufficient response, adverse effects, comorbidities, poor adherence, or patient preference.

Key points: See Table 4 in original paper.

• For adults with suspected or confirmed immune thrombocytopenia (ITP) and a platelet count <20 × 10⁹/L who present to the emergency department with a critical bleed, the panel made the following recommendations:
• High-dose corticosteroids, such as intravenous (IV) dexamethasone (40 mg per day for 4 days) or IV methylprednisolone (1 g per day for 3 days), with the goal of achieving a rapid response within 24 to 48 hours and consequently reducing mortality. The panel felt that corticosteroids should be administered in combination with other recommended treatments.
• IV immunoglobulin (IVIG) 1 g/kg for 1 or 2 consecutive days is an appropriate  Rh immunoglobulin (anti-D) 75 μg/kg once may be used as an alternative; however, it is only applicable to nonasplenic Rh-positive patients and has been associated with hemolysis  and disseminated intravascular coagulation. The panel felt that IVIG should be administered in combination with other recommended treatments.
• Platelet transfusion over no platelet transfusion. Ongoing clinical assessment is required to determine how many platelet transfusions are needed. For patients without critical ITP bleeding, platelet transfusions should generally be avoided because they tend not to result in raising the platelet count substantively. The panel felt that platelet transfusion should be administered in combination with other recommended treatments.
• Tranexamic acid over no tranexamic acid. Dosing of tranexamic acid is 1 g IV every 6 to 8 hours for ~3 days. Aminocaproic acid (4-5 g IV over a 1-hour loading dose followed by maintenance dosing or until bleeding is controlled) can be used as an alternative to tranexamic acid. The panel felt that tranexamic acid should be administered in  combination with other recommended treatments. However, ongoing use of tranexamic acid (and other treatments) should be individualized and reassessed depending on thrombotic risk.
• Thrombopoietin receptor agonists (TPO-RA) should be given in combination with other ITP treatments to control hemostasis and prevent rebleeding. Time-to-response for TPO-RA is ~5 days. If a patient with known ITP is already receiving a TPO-RA at the time of the critical bleed, it should be continued. The panel made a strong recommendation for this intervention when it is accessible.  For emergency use, parenteral formulations were preferred over oral formulations. Thus, the panel recommends romiplostim 5 to 10 μg/kg subcutaneously (eg, 1 or 2 vials of 500 μg). Additional weekly doses of romiplostim could be considered.
• The guideline panel suggests not to use recombinant activated factor VII (rFVIIa). rFVIIa could be considered if there are no other options for treatment or if recommended treatments fail to control bleeding.
• The guideline panel suggests urgent splenectomy when other treatments have failed. Splenectomy should be considered if clinically meaningful hemostasis has not been achieved and bleeding remains life-threatening or uncontrolled after the recommended medical treatments have  been used (high-dose corticosteroids, IVIG, platelet transfusions, and tranexamic acid). Laparoscopic splenectomy is generally  preferred over open splenectomy because it has fewer surgical complications. Patients should receive appropriate  vaccinations before or immediately after splenectomy, and  prophylactic antibiotics should be considered for high-risk patients.

Highlights:

• Chemotherapy-induced thrombocytopenia (CIT) is a challenging and common complication of cytotoxic chemotherapy in patients with gastrointestinal (GI) cancers. There is no widely available approved treatment.
• In this multicenter, US, randomized, placebo-controlled trial, avatrombopag (second generation oral thrombopoietin receptor agonist) was efficacious in the management of persistent CIT in patients with GI cancers.

The trial was closed to enrollment by the data and safety monitoring board at the planned interim analysis after meeting prespecified stopping criteria for efficacy. Sixteen of 23 patients (70% [95% CI, 47 to 87]) receiving avatrombopag achieved  the primary end point versus 4/24 patients (17% [95% CI, 5 to 37]) receiving placebo (P<0.001). The median (interquartile range) platelet count at the end of the on cycle treatment period was 157 (136-202) x 10⁹ /L with avatrombopag versus 72 (68-134) x 10⁹ /L with placebo. Adverse events (AEs) and serious AEs occurred in 78% and 17% of patients receiving avatrombopag and 46% and 0% of patients receiving placebo, respectively. There were no treatment-related AEs leading to death or discontinuation of study drugs.

Key points:

• Primary mediastinal B-cell lymphoma (PMBCL) is a distinct clinicopathological entity within the spectrum of aggressive B-cell lymphomas, characterised by unique clinical, immunophenotypic and molecular features.
• Offer participation in a clinical trial wherever possible.
• Offer R-CHOP-14×6 or DA-R-EPOCH ×6.
• R-CHOP-21 is not recommended.
• Thromboprophylaxis is recommended in view of the high thrombotic risk.
• Anti-microbial prophylaxis is recommended as per local practice.
• Most patients will not require central nervous system (CNS) prophylaxis in view of their low CNS International prognostic index (IPI) score and low risk profile.
• Key updates include the use of positron emission tomography (PET-adapted approaches to guide radiotherapy decisions following first-line chemoimmunotherapy, with omission of consolidative radiotherapy in patients achieving complete metabolic response (Deauville score [DS] 1–3 following chemoimmunotherapy).
• Re-biopsy is recommended if feasible for all DS 4 and DS 5 patients at the end of treatment (EOT).
• Multidisciplinary team (MDT) discussion is essential to review the following:
• The heterogeneity of the DS4 group—there is more concern regarding patients with SUV (standardized uptake value) nearly 2x that of liver compared to just above liver.
• The site of disease and risk of radiotherapy.
• Patient factors such as age and sex.
• There are no current data to support a change of treatment as a result of interim PET response; therefore, the modality of interim imaging should be as per local clinical practice to assess response.
• A personalised approach to balance the risk versus benefit of surveillance PET-computed tomography (PET-CT) or radiotherapy consolidation is required for patients with DS 4 at EOT.
• Patients with DS 4 at EOT should be offered consultation with a clinical (radiation) oncologist to discuss radiotherapy versus surveillance imaging.
• Discuss all patients with DS 5 at EOT at an MDT and perform a biopsy if possible
• Offer systemic treatment as for relapsed disease for patients with DS 5 (See Figure 5 in original paper).
• Radiotherapy alone can be considered if there is limited single residual. uptake on PET-CT without progression or if the patient is unfit for systemic chemotherapy.
• Offer CD19-directed targeted chimeric antigen receptor (CAR) T-cell (CAR-T) therapy (liso-cel) as second-line treatment if the patient has relapsed within 12months.
• Offer CD19-directed CAR-T therapy (axi-cel or liso-cel) as third or subsequent treatment line.
• If available, consider the unlicensed combination of a PD1 inhibitor with brentuximab vedotin for patients with disease progression following CAR-T or autologous transplant.
• Consider radiotherapy to localised sites of chemotherapy refractory disease.
• Consider CD20-directed bispecific antibodies with epcoritamab or glofitamab as a third or subsequent line of treatment.
• Consider loncastuximab as a third or subsequent line of treatment.
• Consider allogeneic transplant for occasional patients who have failed multiple lines of treatment including CAR-T.
• Consider discharge back to primary care for patients who are 24 months following EOT and who remain in remission.
• Potential long-term complications should be outlined to patients and primary care health care professionals.
• Do not perform surveillance imaging in asymptomatic patients.

Highlights:

• Eltrombopag combined with horse antithymocyte globulin and cyclosporine A (CSA) is the standard of care for patients with severe aplastic anemia who are not eligible for stem cell transplantation.
• No consensus exists on the optimal treatment of moderate aplastic anemia (MAA).
• Adding eltrombopag to CSA for first-line treatment of MAA significantly improves trilineage hematologic response at week 24 and addition of eltrombopag in patients without complete response (CR) after 24 weeks of single agent CSA treatment also significantly improves the overall response rate (ORR).

The “Eltrombopag for MAA” (EMAA) trial (ClinicalTrials.gov identifier: #NCT02773225) is an investigator-initiated, prospective, randomized, placebo-controlled, double-blind, multicenter, phase III trial which compared eltrombopag+CSA (n=41) with placebo+CSA (n=44) as a first-line therapy for MAA patients with clinically significant cytopenia. In patients with evaluable response at week 24 (n=75), the ORR, including partial response and CR, was significantly higher in the eltrombopag+CSA arm (71.4%; 95% CI, 54.8%-83.8%) than in the placebo+CSA arm (42.5%; 95% CI, 28.5%-57.8%) (Fisher’s exact P=0.011; primary endpoint). After response assessment at week 24 and unblinding, patients in the placebo arm without CR were switched to receive eltrombopag in addition to continued CSA. This group achieved an ORR of 73.5% by week 48 (McNemar P=0.009, comparing response at 24 vs. 48 weeks). Relapse rate and failure-free survival did not differ significantly among the arms. Eltrombopag was well tolerated without new safety concerns.

Key points:

• Classic myeloproliferative neoplasms, including essential thrombocythemia, polycythemia vera, and primary myelofibrosis, are chronic, clonal hematopoietic stem cell
• These disorders are driven by gain-of-function mutations in the genes Janus kinase 2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL) that activate cytokine signaling (See Figure 1 in original paper). These mutations arise decades before clinical disease develops and confers a clonal advantage that is further shaped by co-mutations in epigenetic, splicing, or signaling genes (See Figure 2 in original paper). Inflammation enhances clonal dominance, favoring the development of myelofibrosis and thrombotic complications.
• Disease evolution may culminate in secondary acute myeloid leukemia, which has a poor prognosis.
• Current therapies primarily aim to control symptoms, thrombosis, and splenomegaly, but they have limited disease-modifying effects, except for pegylated interferon alfa and JAK2 inhibitors in some patients (See Figure 3 in original paper).

1. Essential thrombocythemia: risk stratification according to IPSET-thrombosis:

• Low-risk mutant CALR (Type 1) = Wait and see.
• JAK2 V617F, mutant MPL or high risk mutant CALR (Type 2); Age >60 years, Platelets >1500×10⁹/liter, Vascular events, Cardiovascular risk factors = Aspirin except if platelets >1500×10⁹/liter or if acquired von Willebrand disease AND Hydroxyurea; Pegylated interferon alfa; Anagrelide (second line).
• Polycythemia vera: All patients (Low risk). Keep hematocrit level <45% = Aspirin. Phlebotomy.
• High risk: >60 years. History of thrombosis, Splenomegaly symptoms. Increasing leukocytosis. Uncontrolled hematocrit. Relevant cardiovascular risk factors = Hydroxyurea; Pegylated interferon alfa; JAK inhibitors (Ruxolitinib).

1. Primary myelofibrosis: Stratification of prognostic and individual factors. Prognostic scoring systems

• Low risk and intermediate-1 risk = Wait and see AND Hydroxyurea; Pegylated interferon alfa; Aspirin if plastelets >400×10⁹/liter and <100×10⁹/liter.
• Intermediate-2 and high-risk = JAK inhibitors (Ruxolitinib; Fedratinib; Pacritinib; Momelotinib); hematopoietic stem-cell transplantation.
• Emerging therapies that selectively target mutant CALR and JAK2 V617F using immunotherapy and selective inhibitors could be a breakthrough in the treatment of persons with myeloproliferative neoplasms, with the expectation of achieving durable disease modification and potentially clonal eradication.