Hordes of classical and malignant hematologists returned to the tranquil city of San Diego for the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition this past December. The packed agenda lit the Gaslight District up with neuron-searing data, creating an environment for serotonin-releasing discussions. In search of a theme for my ASH 2023 experience as I considered this supplement, I reminisced about my childhood doing the limbo while roller skating. It was a daring move then and an impossible feat for me now. As I meandered on foot, not on wheels, through the oral and poster sessions, my thoughts were filled with the numerous disease states where we are altering the response bar—in effect, doing a therapeutic limbo. Below are short summaries of some of the data from this meeting that are testing the bar and stretching our practice patterns.
Doing the Limbo in Multiple Myeloma
How low can you go in front-line induction therapy for symptomatic multiple myeloma? As we continue to see the lowering of the bar for undetectable measurable residual disease (MRD) (10-5 or 10-6), we are left questioning the size of the bar (quadruplet vs triplet therapy), as well as the structure (carfilzomib, lenalidomide, and dexamethasone [KRd] vs lenalidomide, bortezomib, and dexamethasone [RVd]).
GUEST EDITOR
Matthew Lunning, DO, FACP
Gay and colleagues presented the phase III IsKia trial to inform practice further.1 The IsKia trial supplemented isatuximab-irfc, a monoclonal antibody directed against CD38, with KRd (Isa-KRd) and compared the quadruplet with KRd during both induction and consolidation (Isa-KRd vs KRd) post high-dose melphalan and autologous stem cell rescue consolidation. The investigators noted significantly more subjects going under the 10-5 bar (77% vs 67%; hazard ratio [HR] = 1.67; P = .049) after consolidation, which was maintained in all assessment phases without an increase in reported toxicity. How these data will impact the first-line landscape given the PERSEUS trial result presented by Sonneveld and colleagues is yet to be seen.2
Doing the Limbo in Acute Myeloid Leukemia
How low do you need to go to defer consolidative allogeneic stem cell transplantation in acute myeloid leukemia (AML)? We continue to see the AML space rapidly evolve with the introduction of targeted agents against poor-risk features like FLT3-ITD. It remains of value to assess whether there are historical data sets that can assist in informing the often life-altering decision of consolidative stem cell transplantation in first complete remission.
An assessment of a subset of subjects enrolled in the prospective trials of AML17 and AML19 was reported by Othman and colleagues to assess molecular MRD status and outcomes to allogeneic transplantation.3 In the AML17 study, the criteria for proceeding to allogeneic transplantation predated MRD assessment. Building on the AML17 experience, the AML19 study recommended allogeneic stem cell transplantation in first complete remission only for NPM1-mutated subjects who had MRD in the peripheral blood after two cycles of therapy.
With the data sets combined, 737 subjects had NPM1 mutation within the AML17/AML19 trials. All 737 subjects had obtained a complete remission or complete remission with incomplete blood cell count recovery after two cycles with available MRD assessment; MRD rates were 17% and 21%, respectively. The study then compared the outcomes of patients with detectable MRD vs undetectable MRD and their post–allogeneic transplantation outcomes. It was concluded that molecular MRD can assist in the discussion to defer consolidative allogeneic stem cell transplantation if MRD is undetectable in the peripheral blood at the end of two treatment courses, including in the NPM1-mutated FLT3-ITD cohort.
Doing the Limbo in Chronic Lymphocytic Leukemia
How low do you need to go to better risk-adapt a fixed-duration regimen in chronic lymphocytic leukemia (CLL)? We continue to see impressive longer-term data in the front-line setting for CLL with either BCL2-based fixed-duration regimens or BTK inhibitor–based regimens with or without anti-CD20 continuous treatments. Multiple prospective data sets continue to mature with the combination of BTK inhibitors and BCL2 inhibitors, with various assessments of MRD.
Hillmen and colleagues reported the extended results of the FLAIR trial with an adapted duration of the covalent BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax.4 In this trial, all subjects were treatment-naive, required treatment based on International Workshop on Chronic Lymphocytic Leukemia criteria, and were considered to be fit for fludarabine, cyclophosphamide, and rituximab (FCR). In this instance, the combination regimen had an ibrutinib lead-in followed by a dose ramp of venetoclax. The ibrutinib-plus-venetoclax treatment duration was MRD-driven, with a minimal dosing for 2 years and a maximum dosing of 6 years. MRD was assessed in the peripheral blood at 12 months and then every 6 months; if MRD was undetectable, the test was conducted again in the peripheral blood and bone marrow at 3 and 6 months, and if all continued to be negative, ibrutinib plus venetoclax would be stopped. With a median follow-up of nearly 44 months, there was a statistically superior 3-year progression-free survival in favor of ibrutinib plus venetoclax compared with FCR (HR = 0.13, 95% confidence interval [CI] = 0.07–0.24); P < .0001).
Doing the Limbo in Gastric MALT Lymphoma
How low can you go regarding a cumulative dose of radiation therapy for localized treatment of Helicobacter pylori–negative gastric MALT (mucosa-associated lymphoid tissue) lymphoma? Although we continue to see excellent results with 24 Gy as the standard dose for definitive localized radiation therapy, risk-adapted approaches—defined by lower doses and duration of radiation therapy of 2 Gy given over 2 consecutive days (the BOOM-BOOM regimen)—are being considered for patients with localized or advanced-stage disease, with higher doses and durations reserved for those with refractory or relapsed disease.
Gunther and colleagues reported a prospective 24-patient experience with a cumulative dose of 4 Gy given as 2-Gy fractions.5 With this approach, 16 of the 24 patients (67%) experienced a complete response at first evaluation, and an additional 4 patients had disease conversion to a complete response over time without further intervention. With a short follow-up of 3 years for local control, 76% of the patients remain with a complete response. The investigators reported one local relapse, with a complete response achieved with further radiation therapy. This radiation strategy likely remains an option for other MALT lymphomas not arising in the stomach.
Doing the Limbo in Diffuse Large B-Cell Lymphoma
How low can you go regarding exposure to anthracycline-based chemotherapy for advanced-stage diffuse large B-cell lymphoma (DLBCL)? We continue to see several active single agents in relapsed or refractory DLBCL moving to the front-line setting in clinical trials, either as additions to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or Pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, prednisone).
Westin and colleagues have taken a different approach in the Smart Stop trial with the initial abandonment of standard anthracycline-based induction therapy and a strategic substitution with the LTRA (lenalidomide, tafasitamab, rituximab, and acalabrutinib) regimen.6 In a risk-adapted approach, those with a metabolic complete response to four cycles of LTRA received two further cycles of LTRA plus CHOP and finished out with four cycles of LTRA. Patients who did not achieve an initial metabolic complete response cohort received LTRA plus CHOP for six cycles. Among the initial 30 patients who completed four cycles of LTRA, an interim positron-emission tomography/computed tomography assessment noted 19 (63%) achieved a metabolic complete response. No patients experienced primary disease progression during the LTRA portion. The 11 patients who did not achieve a metabolic complete response with LTRA received two cycles of LTRA plus CHOP, with two patients not achieving a metabolic complete response. To date, there have been no disease progression events, and the overall response rate was 100%.
DISCLOSURE: Dr. Lunning has had a consulting or advisory role with AbbVie, Acrotech, ADC Therapeutics, Astellas, AstraZeneca, BMS, CRISPR Therapeutics, Daiichi Sankyo/Lilly, EUSA Pharma, Fate Therapeutics, Genentech, Genmab, InstilBio, Ipsen, Kite Pharma, Loxo, Miltenyi Biotec, MorphoSys, Novartis, Nurix Therapeutics, Pharmacyclics, Regeneron, Sana Therapeutics, Sanofi, Seagen, TG Therapeutics, and Takeda; and has received research funding from Celgene and Curis.
REFERENCES
1. Gay F, Roeloffzen W, Dimopoulos MA, et al: Results of the phase III randomized IsKia trial: Isatuximab-carfilzomib-lenalidomide-dexamethasone vs carfilzomib-lenalidomide-dexamethasone as pre-transplant induction and post-transplant consolidation in newly diagnosed multiple myeloma patients. 2023 ASH Annual Meeting & Exposition. Abstract 4. Presented December 10, 2023.
2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al: Phase 3 randomized study of daratumumab + bortezomib, lenalidomide, and dexamethasone (VRd) versus VRd alone in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplantation: Primary results of the PERSEUS trial. 2023 ASH Annual Meeting & Exposition. Abstract LBA-1. Presented December 12, 2023.
3. Othman J, Potter N, Ivey A, et al: The benefit of allogeneic transplant in 1st complete remission in NPM1-mutated AML with or without FLT3 ITD is restricted to those testing MRD-positive after induction: An analysis of the UK NCRI AML17 and AML19 studies. 2023 ASH Annual Meeting & Exhibition. Abstract 425. Presented December 10, 2023.
4. Hillmen P, Cairns DA, Bloor AJC, et al: Ibrutinib plus venetoclax with MRD-directed duration of treatment is superior to FCR and is a new standard of care for previously untreated CLL: Report of the phase III UK NCRI FLAIR study. 2023 ASH Annual Meeting & Exposition. Abstract 631. Presented December 10, 2023.
5. Gunther J, Xu J, Bhutani MS, et al: Ultra low dose 4 Gy radiation for definitive therapy of gastric MALT lymphoma. 2023 ASH Annual Meeting & Exposition. Abstract 298. Presented December 9, 2023.
6. Westin J, Steiner RE, Chihara D, et al: Smart Stop: Lenalidomide, tafasitamab, rituximab, and acalabrutinib alone and with combination chemotherapy for the treatment of newly diagnosed diffuse large B-cell lymphoma. 2023 ASH Annual Meeting & Exposition. Abstract 856. Presented December 11, 2023.
