Syed A. Abutalib, MD
Here is a brief look at the study findings and clinical implications of several recent clinical trials on newer treatment options in neoplastic hematology. Attention is focused on several types of leukemia, Hodgkin lymphoma, and multiple myeloma.
Clinical Trial: INO-VATE ALL phase III trial, in which adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were randomized to receive inotuzumab ozogamicin (n = 109) or standard intensive chemotherapy (n = 109)1
Question Asked: Does inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, result in better outcomes in patients with relapsed or refractory ALL compared with standard therapy? The primary endpoints were complete remission (including complete remission with incomplete hematologic recovery) and overall survival.
Study Conclusion: The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7%; 95% confidence interval [CI]: 72.1%–87.7%) vs 29.4% (95% CI: 21.0%–38.8%, P < .001). Among the patients who achieved complete remission, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts; 78.4% vs 28.1%, P < .001); the duration of remission was longer in the inotuzumab ozogamicin group (median, 4.6 months [95% CI: 3.9–5.4] vs 3.1 months [95% CI: 1.4–4.9]; hazard ratio (HR) = 0.55 (95% CI: 0.31–0.96; P = .03).
In the survival analysis of this study, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5.0 months [95% CI: 3.7–5.6] vs 1.8 months [95% CI: 1.5–2.2]; HR = 0.45 [97.5% CI: 0.34–0.61]; P < .001); the median overall survival was 7.7 months (95% CI: 6.0–9.2) vs 6.7 months (95% CI: 4.9–8.3), and the hazard ratio was 0.77 (97.5% CI: 0.58–1.03; P = .04).
In the safety analysis, the most frequent grade 3 or higher nonhematologic adverse events with inotuzumab ozogamicin were liver-related. Sinusoidal obstruction syndrome of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy.
Clinical Implications: Inotuzumab ozogamicin seems to be a better choice relative to standard intensive chemotherapy, but relapse remains a major concern with both treatments. Therefore, subsequent platforms of curative therapy such as allogeneic hematopoietic cell transplant or T-cell therapy are attractive approaches in an appropriately selected group of patients. At present, a higher risk of sinusoidal obstruction syndrome with inotuzumab ozogamicin is a greater deterrent for patients being considered for allogeneic hematopoietic cell transplant compared with standard therapy.
Clinical Trial: CLL10 is the phase III multicenter, open-label noninferiority trial in which first-line chemoimmunotherapy with bendamustine and rituximab (Rituxan; BR) was compared with fludarabine, cyclophosphamide, and rituximab (FCR) in patients with advanced chronic lymphocytic leukemia (CLL)2
Question Asked: Should FCR continue to be favored over the potentially less toxic BR regimen? The primary endpoint was progression-free survival, with the objective to assess noninferiority of BR (n = 279) to FCR (n = 282).
Study Conclusion: After a median observation time of 37.1 months (interquartile range, 31.0–45.5), median progression-free survival was 41.7 months (95% CI: 34.9–45.3) with BR and 55.2 months (95% CI: not evaluable) with FCR (HR = 1.643; 90.4% CI: 1.308–2.064). As the upper limit of the 90.4% confidence interval was greater than 1.388, the null hypothesis for the corresponding noninferiority hypothesis was not rejected.
Clinical Implications and Considerations: In adults (defined in this study as between the ages of 33 and 81) without comorbidities, FCR appeared to be superior to BR as first-line therapy for patients with CLL without the 17p deletion. It is important to note that the infectious complications and secondary malignancies were more pronounced in the FCR arm than in the BR arm for adult CLL patients older than 65 years.
Clinical Trial: Adapted treatment guided by interim (after two cycles of ABVD [doxorubicin, bleomycin, vinblastine, dacarabazine] of a planned six cycles) PET-CT (positron-emission tomography–computed tomography) scan in advanced Hodgkin lymphoma.3 In this particular study, advanced Hodgkin lymphoma was defined as Ann Arbor stage IIB to IV disease or stage IIA disease with adverse features, such as bulky disease (> 33% of the transthoracic diameter or > 10 cm elsewhere) or at least three involved sites by Hodgkin lymphoma.
Question Asked: Can negative (defined as a score of ≤ 3 on the Deauville 5-point scale) interim PET-CT scan safely allow omission of bleomycin in the remaining four cycles of therapy? The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of five or more percentage points. Patients with negative interim PET-CT after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles three through six.
Study Conclusion: With a median follow-up of 41 months, the 3-year progression-free survival and overall survival in the ABVD group were 85.7% (95% CI: 82.1%–88.6%) and 97.2% (95% CI: 95.1%–98.4%), respectively; the corresponding rates in the AVD group were 84.4% (95% CI: 80.7%–87.5%) and 97.6% (95% CI: 95.6%–98.7%). The absolute difference in the 3-year progression-free survival (ABVD minus AVD) was 1.6 percentage points (95% CI: –3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group.
Clinical Implications and Considerations: Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative (≤ 3 on 5-point Deauville criteria) interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy. Whether or not this should now be considered the standard of care in all patients is less clear, in light of the surprisingly low incidence of serious toxic effects in both groups of this study.3,4 However, de-escalation may be considered in certain groups of patients at higher risk of bleomycin-induced pulmonary toxicity (ie, patients older than 40 years of age, active or chronic smokers, or patients with decreased renal function or underlying pulmonary disease). Finally, longer follow-up will be required to establish whether reduction in the use of bleomycin may affect long-term morbidity and mortality.3
Clinical Trial: In the multicenter, open-label, phase III CASTOR trial, 498 patients with relapsed or relapsed and refractory multiple myeloma were randomized to receive up to 8 cycles of bortezomib (Velcade) and dexamethasone (control group) or bortezomib and dexamethasone in combination with daratumumab (Darzalex; daratumumab group)5
Question Asked: Would adding daratumumab to the combination of bortezomib and dexamethasone improve progression-free survival in these patients with resistant multiple myeloma?
Study Conclusion: A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group vs 26.9% in the control group. The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs 63.2%, P < 0.001), as were the rates of very good partial response or better (59.2% vs 29.1%, P < .001) and complete response or better (19.2% vs 9.0%, P = .001).
Clinical Considerations: Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients who received this agent. These reactions, which were mostly grade 1 or 2 (grade 3 in 8.6% of patients) and occurred during the first infusion in 98.2% of patients, were easily manageable. Despite such remarkable findings on progression-free-survival with triple therapy in relapsed and refractory multiple myeloma, one should be reminded that patients were excluded from the study if they had disease that was refractory to proteasome inhibitors including bortezomib or unacceptable toxicity from prior exposure to bortezomib. ■
Disclosure: Dr. Abutalib reported no potential conflicts of interest.
Dr. Abutalib is Assistant Director, Hematology & Bone Marrow Transplantation Service, Cancer Treatment Centers of America, Zion, Illinois. He also is the guest editor of The ASCO Post’s “Hematology Expert Review,” an occasional feature that includes a case report detailing a particular hematologic condition followed by questions, answers, and expert commentary.
1. Kantarjian HM, DeAngelo DJ, Stelljes M, et al: Inotuzumab ozogamicin vs standard therapy for acute lymphoblastic leukemia. N Engl J Med 375:740-753, 2016.
2. Eichhorst B, Fink AM, Bahlo J, et al: First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10). Lancet Oncol 17:928-942, 2016.
3. Johnson P, Federico M, Kirkwood A, et al: Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med 374:2419-2429, 2016.
4. Bartlett NL: Fine-tuning the treatment of Hodgkin’s lymphoma. N Engl J Med 374:2490-2492, 2016.
5. Palumbo A, Chanan-Khan A, Weisel K, et al: Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 375:754-766, 2016.