Mature T- and NK-cell neoplasms

In Western countries, mature T- and natural killer (NK)-cell neoplasms (MTNKN) comprise less than 15% of all non-Hodgkin lymphomas (NHL). The prognosis for patients diagnosed with MTNKN remains poor, with 5-year overall survival (OS) reported to be under 50%. Little is known about risk factors for central nervous system (CNS) relapse in MTNKN. A study recently described the clinical epidemiology of CNS relapse in patients with MTNKN and the development of the CNS relapse in T-cell lymphoma index (CITI) to predict patients at highest risk of CNS relapse. The authors reviewed data from 135 patients with MTNKN and CNS relapse which were pooled with non-CNS relapse control patients. Using a complete case analysis (N=182), of whom 91 had CNS relapse, they applied a Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort (N=566). 

CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (PTCL NOS, 25%). Median time to CNS relapse was 8 months and median OS after CNS relapse was 4.7 months. Validation set patients with low-risk (N=158) and high-risk (N=188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio [HR] 5.24, 95% confidence interval [CI], 1.50-18.26, p=0.018). 

Acute lymphoblastic leukemia

Acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is a major cause of disease progression in newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I. Results from PhALLCON, a global registrational phase 3, open-label trial (NCT03589326) were recently published. It compared patients randomized 2:1 to ponatinib plus reduced-intensity chemotherapy (induction: vincristine, dexamethasone; consolidation: methotrexate; maintenance: vincristine, prednisone) (n=154) versus imatinib plus reduced-intensity chemotherapy (n=78), followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial, in adults with newly diagnosed Ph+ ALL (eFigure 1. Supplemental Online Content). 

Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) were analyzed for the primary end point which was minimal residual disease (MRD)-negative complete remission rate (≤0.01% BCR::ABL1 [MR4]) with complete remission maintained for at least 4 weeks at the end of cycle 3. This (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs. imatinib (16.7% [13/78]) (risk difference, 0.18 [95% confidence interval [CI], 0.06-0.29]; p= 0.002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Ponatinib’s benefit over imatinib for reaching MRD-negative complete remission was consistent across all subgroups evaluated. 

Acute myeloid leukemia

The decision of which patients with NPM1-mutated acute myeloid leukemia (AML) should get an allogeneic transplant during first complete remission (CR1-allo) is still debatable. Measurable residual disease (MRD) status is used by some facilities as a transplant indication, whereas baseline FLT3–internal tandem duplication (ITD) is used by others. A study was recently published that examined the impact of CR1-allo according to peripheral blood NPM1 MRD status measured (real-time quantitative polymerase chain reaction) after 2 courses of induction chemotherapy. Of 737 patients achieving remission, MRD was positive in 19%. CR1-allo was performed in 46% of MRD⁺ and 17% of MRD⁻ patients. They observed significant heterogeneity of overall survival (OS) benefit from CR1-allo according to MRD status, with substantial OS advantage for MRD⁺ patients (3-year OS with CR1-allo vs. without: 61% vs. 24%; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.24-0.64; p<0.001) but no benefit for MRD⁻ patients (3-year OS with CR1-allo vs. without: 79% vs. 82%; HR, 0.82; 95% CI, 0.50-1.33; p=0.4).  In patients with coexisting FLT3-ITD, again CR1-allo only improved OS for MRD⁺ patients (3-year OS, 45% vs. 18%; compared with 83% vs. 76% if MRD^-); no interaction with FLT3 allelic ratio was observed.  The accompanying commentary to this study proposes a management algorithm in this scenario.

Acute lymphoblastic leukemia

Two simultaneous publications have recently been released: the recommendations from the European LeukemiaNet (ELN) working group for (1) diagnosis, prognostic factors, and assessment and (2) management of adult acute lymphoblastic leukemia (ALL).  The latter covers treatment approaches, including the use of new immunotherapies, application of minimal residual disease (MRD) for treatment decisions, management of specific subgroups, and challenging treatment situations as well as late effects and supportive care.  Here is a summary of the initial therapeutic approach of Philadelphia chromosome (Ph)-negative ALL.

Therapy in Ph-negative ALL
Pediatric-based chemotherapy in adult ALL as standard of care (SoC). The typical compounds are corticosteroids (especially dexamethasone [Dexa]), vincristine, antimetabolites (6-thiopurines, cytarabine, and methotrexate [MTX]) and asparaginase (ASP; pegylated [PEG-ASP] or not) plus intensive supportive care, avoidance of inappropriate dose reductions/delays and a risk-adapted stem cell transplantation (SCT).

Induction:

·       Pre-phase with corticosteroids for 5 to 7 days; other drugs are occasionally added, for example, cyclophosphamide (CP).

·       Intrathecal (IT) prophylaxis after sampling of cerebrospinal fluid (CSF). MTX, cytarabine (AC), and steroids can all be safely administered, and all have been used either singly or in combination, with no clear benefits to any specific IT regimen.

·       Support with granulocyte colony-stimulating factor transfusions and optimal prophylaxis and management of infections.

·       The induction backbone consists of vincristine, steroids, an anthracycline, and ASP.

·       The second induction or first consolidation consists usually of CP, AC and mercaptopurine (MP) or high-dose methotrexate (HD-MTX)/HD-AC. HD-AC/idarubicin can be used as salvage. The few patients failing to enter complete remission (CR) after 2 induction courses have highly resistant ALL and are candidates for alternative immunotherapies, depending on the protocol.

Consolidation:  Consolidation is administered to patients in CR. Outcome is best with rotational multidrug cycles consisting of HD-MTX and HD-AC, PEG-ASP, and  other drugs. The average duration of consolidation is ≥6 months, for 6 to 8 total courses.  Given the heterogeneous consolidation protocols, the comparable results after adjustment for patient age and risk class, and the lack of randomized comparisons, at present no single regimen can be recommended as SoC for Ph-negative ALL. Pediatric-based regimens are favored. It is strongly recommended to participate in (or adopt) prospective clinical trials. Experience and established guidelines at the sites are important for adoption of distinct protocols.

Frontline targeted therapy of Ph-negative B-ALL:  evidence is accumulating rapidly that immunotherapy can improve antileukemic efficacy. Anti-CD20 antibodies (rituximab), the bispecific CD19/CD3 antibody blinatumomab (Blina) and the CD22 antibody-drug conjugate inotuzumab ozogamicin (InO) have been integrated into frontline and salvage regimens in clinical trials. Overall, the use of rituximab is recommended for the management of CD20+ ALL, for at least 8 doses. Similarly, because of the favorable early results and high expectations with upfront InO and Blina in CD22+ and CD19+ B-ALL, participation in InO and Blina trials for untreated patients is recommended until results from ongoing studies are available. The concurrent use of an anti-CD20 antibody in CD20+ ALL represents the SoC as well as the use of Blina in case of molecular failure.

Maintenance therapy: maintenance therapy is strongly recommended for all patients. Maintenance therapy has not been tested in randomized trials but any attempts to omit maintenance have resulted in inferior outcomes. MP and MTX are the main drugs used in maintenance. Intermittent IT prophylaxis is part of most regimens. Some groups include other compounds such as the POMP regimen (MP, MTX, prednisone, and vincristine), but the benefit is debated. In addition, data on a potential benefit of vincristine or steroid pulses in pediatric patients with IKZF1 are controversial. The use of Dexa instead of prednisone in maintenance may lead to an increased incidence of infection-related deaths. Therefore, maintenance without vincristine or steroid pulses is preferred by most groups. A total treatment duration of 2 to 2.5 years including maintenance is recommended. Intervals of ~3 months are suggested for MRD testing during maintenance.

MRD-based treatment modification

Overall, patients with MRD>0.01% after 3 blocks of standard therapy have an indication for SCT and for targeted therapies. To date, there is no evidence that treatment reduction, except for omission of SCT, can be recommended outside of clinical trials in patients with a favorable course of MRD. Whether SCT can be omitted in all patients with molecular CR, including those in specifically unfavorable subgroups, should be investigated. After conversion from MRD positive to MRD negative status using new compounds such as Blina, subsequent SCT remains the SoC in younger patients with a matched donor.

SCT

Overall, indication for SCT is weighed against the reduction of the relative risk and the risk of treatment-related mortality. Despite attempts to elaborate prognostic scores, the potential benefit in many individual cases is uncertain. The role of autologous (auto) SCT appears questionable and is mainly affected by the MRD status.  Donor type choice does not differ from other leukemias. In case of limited access to total body irradiation or for patients who cannot tolerate this procedure, conditioning based on intravenous busulfan or HD thiotepa may be an alternative. For older patients, reduced-intensity conditioning should be considered, preferably within clinical trials.

Subsequently, the recommendations focus on: treatment of specific subgroups (Adolescents and young adults; Older patients (>55-65 years); Ph/BCR::ABL1-positive (Ph+) ALL; Ph-like ALL; T-ALL; Lymphoblastic lymphoma (LBL), relapsed/refractory ALL and management of specific situations.

Multiple myeloma

Smoldering multiple myeloma (SMM) constitutes a heterogeneous clinicopathological entity with some patients showing an indolent course (“monoclonal gammopathy of unknown significance [MGUS]‐like”) while others have a more aggressive behavior with a rapid progression to multiple myeloma (MM [“early MM”]).The most frequently used risk score in clinical practice to assess the likelihood of developing symptomatic MM from SMM is the 2/20/20 model validated in 2020 by the International Myeloma Working Group (IMWG). Its primary limitation is that the risk score is applied at the time of diagnosis and cannot be modified. A recent study aimed to determine if identifying an evolving pattern in serum M protein (SMP) enhances the identification of high-risk individuals, as a dynamic, accurate patient risk assessment for progression. Eighty‐three patients diagnosed with SMM were included. Patients were initially classified according to the 2/20/20 IMWG score at baseline and later reclassified depending on the presence of an SMP evolving pattern, into six groups (the evolving pattern was considered when a progressive increase of SMP size by at least 10% was observed in those with a baseline SMP of 3 g/dL or higher, while a 25% increase was required for those with a baseline SMP below 3 g/dL, always confirmed in a second measurement). The authors regrouped the patients into three final risk groups: low‐risk, intermediate‐risk, and high‐risk. The risk of progression at two years for the high‐risk group was 88% and all patients had progressed at 4 years. The performance measurements were superior using the new 2/20/20‐Evolving score independently for the detection of high‐risk patients.