Syed A. Abutalib, MD
HERE IS A BRIEF LOOK at the study findings and clinical implications of several recent and important clinical trials in neoplastic hematology. Attention is focused on clonal myeloid disorders, acute lymphoblastic leukemia, lymphoma, and plasma cell dyscrasias.
Clonal Myeloid Disorders
STUDY: Clonal hematopoiesis of indeterminate potential increases the risk of atherosclerotic cardiovascular disease.1
Key Findings: The researchers used whole-exome sequencing to detect the presence of clonal hematopoiesis of indeterminate potential in peripheral blood cells and associated that discovery with coronary heart disease using samples from 4 case-control studies that together enrolled 4,726 participants with coronary heart disease and 3,529 controls.
In nested case-control analyses from 2 prospective cohorts, carriers of clonal hematopoiesis of indeterminate potential had a risk of coronary heart disease that was 1.9 times greater than in noncarriers (95% confidence interval [CI] = 1.4–2.7). In 2 retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with clonal hematopoiesis of indeterminate potential had a risk of myocardial infarction that was 4.0 times greater than in noncarriers (95% CI = 2.4–6.7). Somatic mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. Clonal hematopoiesis of indeterminate potential carriers with these mutations also had increased coronary artery calcification, a marker of coronary atherosclerosis burden.
Clinical Implications: It is prudent to perform preventive cardiovascular risk measures in individuals with a diagnosis of clonal hematopoiesis of indeterminate potential.
Study: Prospective randomized comparison of idarubicin (12 mg/m2 × 3 days; n = 149) and high-dose daunorubicin (90 mg/m2 × 3 days; n = 150) in induction chemotherapy with cytarabine (200 mg/m2 × 7 days) for younger adults with newly diagnosed acute myeloid leukemia (AML)2
Key Findings: Complete remission was induced in 232 patients (77.6%), with no difference in complete remission rates between the idarubicin and high-dose daunorubicin arms (80.5% vs 74.7%, respectively; P = .224). At a median follow-up of 34.9 months, survival and relapse rates did not differ between the idarubicin and high-dose daunorubicin arms (4-year overall survival rate = 51.1% vs 54.7%, respectively, P = .756; cumulative relapse rate = 35.2% vs 25.1%, respectively, P = .194; event-free survival rate = 45.5% vs 50.8%, respectively, P = .772).
Toxicity profiles were also similar in the two arms. Interestingly, overall and event-free survival times of patients with FLT3-ITD mutation were significantly different (idarubicin vs high-dose daunorubicin: median overall survival = 15.5 months vs not reached, respectively, P = .030; event-free survival = 11.9 months vs not reached, respectively, P = .028).
Clinical Implications: This phase III trial comparing idarubicin with high-dose daunorubicin as part of induction therapy in AML did not find significant differences in complete remission rates, relapse, or survival. A significant interaction between the treatment arm and the FLT3-ITD mutation was found, and high-dose daunorubicin was more effective than idarubicin in patients with FLT3-ITD mutation.
Study: Randomized phase II multicenter study of azacitidine alone (n = 92) or in combination with lenalidomide (Revlimid; n = 93) or with vorinostat (Zolinza; n = 92) in higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S11173
Key Findings: Serious adverse events were similar across arms, although patients in the combination arms were significantly more likely to have therapy stopped because of toxicities or complications (8% for azacitidine, 20% for azacitidine plus lenalidomide [P = .05 vs azacitidine], and 21% for azacitidine plus vorinostat [P = .03 vs azacitidine, with P = .02 for both combination arms vs azacitidine]).
With a median follow-up of 23 months (range = 1–43 months), the overall response rate was 38% for patients receiving azacitidine, 49% for azacitidine plus lenalidomide (P = .14 vs azacitidine), and 27% for azacitidine plus vorinostat (P = .16 vs azacitidine). For patients with chronic myelomonocytic leukemia, the overall response rate was higher for azacitidine plus lenalidomide vs azacitidine alone (68% vs 28%, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio [HR] = 1.30, P = .05).
“It is prudent to perform preventive cardiovascular risk measures in individuals with a diagnosis of clonal hematopoiesis of indeterminate potential.”— Syed A. Abutalib, MD
Clinical Implications: Patients with higher-risk MDS treated with azacitidine-based combinations had a similar overall response rate to those treated with azacitidine monotherapy. However, the efficacy of combination regimens in higher-risk MDS may have been affected by non–protocol driven dose modifications and underdosing. Patients with chronic myelomonocytic leukemia treated with azacitidine plus lenalidomide had twice the overall response rate compared with azacitidine alone.
Acute Lymphoblastic Leukemia
STUDY: Early response–based therapy stratification improves survival in patients with adult early thymic precursor acute lymphoblastic leukemia (n = 47) treated on two Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) studies, ie, GRAALL-2003 and GRAALL-2005 studies4
Key Findings: Early thymic precursor ALL blasts have a characteristic immunophenotype, with reduced or absent expression of T-lymphoid markers (CD1a, CD5, CD8) and positivity for at least one hematopoietic stem cell and/or myeloid antigen (CD34, CD117, human leukocyte antigen/antigen D–related [HLA-DR], CD13, CD33, CD11b, CD65). Despite expected high levels of early bone marrow chemotherapy resistance (87%), the overall prognosis for adults with early thymic precursor ALL treated using the GRAALL protocols was not inferior to that of the non–early thymic precursor ALL group (5-year overall survival rate = 59.6% [95% CI = 44.2%–72.0%] for early thymic precursor group, vs 66.5% [95% CI = 58.7%–73.2%] for non–early thymic precursor group; P =.33). Allogeneic hematopoietic cell transplantation (allo-HCT) had a beneficial effect in a large proportion of patients with early thymic precursor ALL.
Clinical Implications: These retrospective data suggest the use of response-based risk stratification and therapy intensification based on early treatment response abrogates the poor prognosis of adult patients with early thymic precursor ALL. The investigators were unable to test whether allo-HCT was beneficial for patients with early thymic precursor achieving molecular remission. Additional studies should also determine whether outcomes may be further improved by treatments targeting pathways that are preferentially mutated in early thymic precursor ALL (eg, JAK-STAT inhibition) or by the addition of nelarabine (Arranon), which is being evaluated in the ongoing current study GRAALL- 2014/T (ClinicalTrials.gov identifier NCT02619630).
“The use of response-based risk stratification and therapy intensification based on early treatment response abrogates the poor prognosis of adult patients with early thymic precursor ALL.”— Syed A. Abutalib, MD
Study: Complete hematologic and molecular response in adult patients with relapsed/refractory BCR/ABL1–positive B-precursor acute lymphoblastic leukemia (pre-B ALL) following treatment with blinatumomab (Blincyto)5
Key Findings: The primary endpoint was complete remission or complete remission with partial hematologic recovery during the first two cycles. Major secondary endpoints included minimal residual disease (MRD) response, rate of allo-HCT, relapse-free survival, overall survival, and adverse events.
Of 45 patients, 16 (36%; 95% CI = 22%–51%) achieved complete remission or partial hematologic recovery during the first 2 cycles, including 4 of 10 patients with the T315I mutation; 88% of complete remission/partial hematologic recovery responders achieved a complete MRD response. Seven responders (44%) proceeded to allo-HCT, including 55% (6 of 11) of transplantation-naive responders. Median relapse-free survival and overall survival were 6.7 and 7.1 months, respectively.
The most frequent adverse events were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Three patients had cytokine-release syndrome (all grade 1 or 2), and three patients had grade 3 neurologic events, one of which (aphasia) required temporary treatment interruption. There were no grade 4 and 5 neurologic events.
Clinical Implications: Single-agent blinatumomab showed antileukemic activity in high-risk patients with BCR/ABL1–positive pre-B ALL who had relapsed or whose disease was refractory to tyrosine kinase inhibitors. Adverse events with this treatment can be serious.
STUDY: REMARC phase III study of lenalidomide maintenance for 2 years compared with placebo in responding older adults (aged 60–80 years) with diffuse large B-cell lymphoma (DLBCL) treated with front-line rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for 6 to 8 cycles. Of note, two cycles of rituximab could be administered after six cycles, at the investigator’s discretion.6
Key Findings: At the time of the primary analysis (December 2015), with a median follow-up of 39 months from random assignment, median progression-free survival was not reached for lenalidomide maintenance vs 58.9 months for placebo (HR = 0.708, 95% CI = 0.537–0.933; P = .01). Most common grade 3 or 4 adverse events associated with lenalidomide vs placebo maintenance were neutropenia (56% vs 22%) and cutaneous reactions (5% vs 1%).
Contrary to prior reports, analysis of outcomes on the basis of cell-of-origin per Hans criteria (which utilizes staining for CD10, BCL6, and MUM1) in patients with DLBCL showed a statistically significant difference in median progression-free survival in favor of lenalidomide (60.9 months; 95% CI = 59.8 months to not reached) over placebo (52.7 months; 95% CI = 40.5 months to not reached) in patients with a germinal center B-cell profile (HR = 0.491, 95% CI = 0.245–0.985; P = .04). However, no significant difference was seen in patients with a non–germinal center B-cell profile (HR = 1.081, 95% CI = 0.670–1.746; P = .75). With a longer median follow-up of 52 months (October 2016), overall survival was similar between the arms (HR = 1.218, 95% CI = 0.861–1.721; P = .26).
Clinical Implications: Presently, I hesitate to conclude the results of this study are practice-changing in older adults with newly diagnosed DLBCL. In my opinion, the reporting of this study has many flaws, and I find it difficult to recommend the maintenance strategy that was investigated.
Study: An international prognostic index for marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT)7 developed from the International Extranodal Lymphoma Study Group (IELSG)-19 randomized trial (n = 401)8 and validated in an independent patient cohort (n = 633)
Key Findings: The three individual factors maintaining the greatest prognostic significance for event-free survival (the main endpoint of the IELSG-19 trial) were age ≥ 70 years (HR = 1.72, 95% CI = 1.26–2.33), Ann Arbor stage III or IV (HR = 1.79, 95% CI = 1.35–2.38), and an elevated lactate dehydrogenase level (HR = 1.87, 95% CI = 1.27–2.77). The prognostic index (MALT-IPI) constructed using these three parameters identified three groups: low (n = 167), intermediate (n = 165), and high (n = 67) risk, corresponding to the presence of 0, 1, or ≥ 2 of these factors, respectively.
The 5-year event-free survival rates were 70% in the low-risk group, 56% in the intermediate-risk group, and 29% in the high-risk group. Five-year overall survival rates were 99%, 93%, and 64%, respectively, showing the greatest discrimination for the high-risk group.
“The MALT [prognostic index] … efficiently discriminates patients with good, intermediate, and poor event-free survival and also proved to be valuable with respect to progression-free, cause-specific, and overall survival.”— Syed A. Abutalib, MD
Clinical Implications: The MALT-IPI, built on the basis of the IELSG-19 trial main endpoint (event-free survival), efficiently discriminates patients with good, intermediate, and poor event-free survival and also proved to be valuable with respect to progression-free, cause-specific, and overall survival. It may help define appropriate treatment approaches for individual patients who are being considered for treatment with one of the three therapies administered in this trial (rituximab plus chlorambucil [Leukeran] vs either chlorambucil or rituximab monotherapy).
Plasma Cell Dyscrasias
STUDY: Treatment of B-cell disorder improves renal outcomes of patients with monoclonal gammopathy–associated C3 glomerulopathy.9
Key Findings: The high frequency of monoclonal gammopathy in adult patients with C3 glomerulopathy emphasizes the role of monoclonal immunoglobulin in the occurrence of renal disease and raises the issue of its therapeutic management. The aim of the present study was to evaluate renal outcomes after chemotherapy in a large cohort of patients with C3 glomerulopathy and monoclonal immunoglobulin.
Fifty adult patients with monoclonal immunoglobulin and biopsy-proven C3 glomerulopathy were extracted from the French national database of C3 glomerulopathy. Investigators retrospectively compared renal outcomes in patients who either received or did not receive chemotherapy targeting the underlying B-cell clone.
At diagnosis, renal disease was severe, with nephrotic-range proteinuria in 20 (43%) of 46 patients and chronic kidney disease ≥ stage III in 42 (86%) of 49 patients. Monoclonal gammopathy was of IgG type in 47 patients (94%). Hematologic diagnosis was monoclonal gammopathy of renal significance in 30 (60%), multiple myeloma in 17 (34%), and chronic lymphocytic leukemia in 3 (6%) patients. Complement studies showed low C3 level in 22 (43%) of 50 and elevated soluble C5b-9 level in 27 (79%) of 34 patients. Patients who achieved hematologic response after chemotherapy had higher renal response rates (P = .0001) and median renal survival (HR = 0.22, 95% CI = 0.05–0.92; P = .009) than those receiving conservative/immunosuppressive therapy.
“Chemotherapy adapted to the B-cell clone may constitute an efficient strategy for C3 glomerulopathy in the setting of monoclonal immunoglobulin.”— Syed A. Abutalib, MD
Clinical Implications: Chemotherapy adapted to the B-cell clone may constitute an efficient strategy for C3 glomerulopathy in the setting of monoclonal immunoglobulin, as rapid achievement of hematologic response appears to result in improved renal survival. However, therapeutic choices should take into account renal elimination of antineoplastic drugs to limit their adverse effects.
Study: Prospective evaluation of magnetic resonance imaging (MRI) and [18F]fluorodeoxyglucose positron-emission tomography–computed tomography (PET-CT) at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 trial: Results of the IMAJEM study10
Key Findings: In this study, 134 patients received a combination of lenalidomide, bortezomib (Velcade), and dexamethasone (RVD) with or without autologous hematopoietic cell transplantation, followed by lenalidomide maintenance. PET-CT and MRI were performed at diagnosis, after three cycles of RVD, and before maintenance therapy. The primary endpoint was the detection of bone lesions at diagnosis by MRI vs PET-CT. Secondary endpoints included the prognostic impact of MRI and PET-CT regarding progression-free and overall survival.
Normalization of MRI after three cycles of RVD and before maintenance was not predictive of progression-free or overall survival. PET-CT became normal after three cycles of RVD in 32% of the patients with a positive evaluation at baseline, and progression-free survival was improved in this group (30-month progression-free survival = 78.7% vs 56.8%, respectively). PET-CT normalization before maintenance was described in 62% of the patients who were positive at baseline. This was associated with better progression-free and overall survival. Extramedullary disease at diagnosis was an independent prognostic factor for progression-free and overall survival, whereas PET-CT normalization before maintenance was an independent prognostic factor for progression-free survival.
Clinical Implications: There is no difference in the detection of bone lesions at diagnosis when comparing PET-CT and MRI. PET-CT is a powerful tool with which to evaluate the prognosis of multiple myeloma. ■
DISCLOSURE: Dr. Abutalib reported no conflicts of interest.
1. Jaiswal S, Natarajan P, Silver AJ, et al: Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 377:111-121, 2017.
2. Lee JH, Kim H, Joo YD, et al: Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol 35:2754-2763, 2017.
3. Sekeres MA, Othus M, List AF, et al: Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol 35:2745-2753, 2017.
4. Bond J, Graux C, Lhermitte L, et al: Early response-based therapy stratification improves survival in adult early thymic precursor acute lymphoblastic leukemia: A Group for Research on Adult Acute Lymphoblastic Leukemia Study. J Clin Oncol 35:2683-2691, 2017.
5. Martinelli G, Boissel N, Chevallier P, et al: Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol 35:1795-1802, 2017.
6. Thieblemont C, Tilly H, Gomes da Silva M, et al: Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 35:2473-2481, 2017.
7. Thieblemont C, Cascione L, Conconi A, et al: A MALT lymphoma prognostic index. Blood 130:1409-1417, 2017.
8. Zucca E, Conconi A, Martinelli G, et al: Final results of the IELSG-19 randomized trial of mucosa-associated lymphoid tissue lymphoma: Improved event-free and progression-free survival with rituximab plus chlorambucil versus either chlorambucil or rituximab monotherapy. J Clin Oncol 35:1905- 1912, 2017.
9. Chauvet S, Frémeaux-Bacchi V, Petitprez F, et al: Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy. Blood 129:1437, 2017.
10. Moreau P, Attal M, Caillot D, et al: Prospective evaluation of magnetic resonance imaging and [18F]fluorodeoxyglucose positron emission tomography-computed tomography at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 trial: Results of the IMAJEM study. J Clin Oncol 35:2911-2918, 2017.