BACKGROUND
The achievement of a 3‐month complete molecular response (CMR) is a major prognostic factor for survival in patients with Philadelphia chromosome (Ph)‐positive acute lymphoblastic leukemia ...(ALL). However, 25% of patients relapse during therapy with tyrosine kinase inhibitors (TKIs).
METHODS
The authors reviewed 204 patients with Ph‐positive ALL who were treated between January 2001 and December 2018 using the combination of hyper‐CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus a TKI (imatinib, 44 patients 22%; dasatinib, 88 patients 43%; or ponatinib, 72 patients 35%). Progression‐free survival (PFS) was defined as the time from the start date of therapy to the date of relapse, death, or last follow‐up. Overall survival (OS) was defined as the time from the start date of therapy to the date of death or last follow‐up.
RESULTS
Overall, a 3‐month CMR was observed in 57% of patients, including 32% of those who received imatinib, 52% of those who received dasatinib, and 74% of those who received ponatinib. The median follow‐up was 74 months (imatinib, 180 months; dasatinib, 106 months; ponatinib, 43 months). Among 84 patients in 3‐month CMR, 17 (20%) proceeded to undergo allogeneic stem cell transplantation (ASCT). The 5‐year PFS and OS rates were 68% and 72%, respectively. By multivariate analysis, ponatinib therapy was the only significant favorable independent factor predicting for progression (P = .028; hazard ratio, 0.388; 95% CI, 0.166‐0.904) and death (P = .042; hazard ratio, 0.379; 95% CI, 0.149‐0.966). ASCT was not a prognostic factor for PFS and OS by univariate analysis.
CONCLUSIONS
In patients with Ph‐positive ALL, ponatinib is superior to other types of TKIs in inducing and maintaining a CMR, thus preventing disease progression. ASCT does not improve outcome once a 3‐month CMR is achieved.
Ponatinib is superior to other types of tyrosine kinase inhibitors in inducing and maintaining a complete molecular response, thus preventing progression in patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia. Allogeneic stem cell transplantation does not improve outcomes once a 3‐month complete molecular response is achieved.
Allogeneic SCT for older patients remains challenging at least in part due to graft-versus-host disease (GVHD) and higher non-relapse mortality (NRM). We conducted a prospective pilot study primarily ...for older patients undergoing matched unrelated donor (MUD) SCT using a reduced-intensity (RIC) melphalan-based conditioning and post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis with tacrolimus and mycophenolate mofetil. Twenty-two patients (median age 64, IQR 58, 66) underwent RIC MUD SCT for high-risk hematological malignancies including AML/MDS (73%), CML/MPD (18%), and other (10%). Two (9%) patients had early death; the rest (100%) engrafted. After a median follow-up of 17 months, 11 patients were alive and disease-free with an estimated 2-year progression-free (PFS) and overall (OS) survival of 48%. The cumulative incidences of grades 2-4 and 3-4 acute GVHD (aGVHD) at day + 100 and 2-years were 32 and 4%, and 59 and 24%, respectively. No cases of chronic GVHD (cGVHD) were noted. However, late acute GVHD was observed in 6 (27%) patients. In conclusion, RIC MUD SCT with melphalan-based conditioning and PTCy-based GVHD-based prophylaxis for older patients appears effective in controlling relapse. While cGVHD was not seen and early aGVHD appears controllable, a significant proportion developed late aGVHD responsible for higher NRM seen in these patients.
In this study, we analyzed the long-term outcome of a risk-adapted transplantation strategy for mantle cell lymphoma in 121 patients enrolled in sequential transplantation protocols. Notable ...developments over the 17-year study period were the addition of rituximab to chemotherapy and preparative regimens and the advent of nonmyeloablative allogeneic stem cell transplantation (NST). In the autologous transplantation group (n = 86), rituximab resulted in a marked improvement in progression-free survival for patients who received a transplant in their first remission (where a plateau emerged at 3-8 years) but did not change the outcomes for patients who received a transplant beyond their first remission. In the NST group, composed entirely of patients who received a transplant beyond their first remission, durable remissions also emerged in progression-free survival at 5 to 9 years. The major determinants of disease control after NST were the use of a peripheral blood stem cell graft and donor chimerism of at least 95%, whereas the major determinant of death was immunosuppression for chronic graft-versus-host disease. Our results show that long-term disease-free survival in mantle cell lymphoma is possible after rituximab-containing autologous transplantation for patients in first remission and after NST for patients with relapsed or refractory disease.
Steroids remain the initial therapy for acute graft-vs.-host disease (AGVHD). Strategies to improve response and minimize steroid exposure are needed. We report results of a randomized, adaptive, ...Bayesian-designed, phase II trial of prednisone with or without extracorporeal photopheresis (ECP) as an initial therapy for patients with newly diagnosed AGVHD. The primary endpoint was success at day 56 defined as: alive, in remission, achieving AGVHD response without additional therapy, and on <1 mg/kg at day 28 and <0.5 mg/kg on day 56 of steroids. Eighty-one patients were randomized to the ECP arm (n = 51) or steroids alone (n = 30). Median age was 54 years (range: 17-75); 90% had grade II AGVHD and 10% had grades III and IV AGVHD, with skin (85%), upper (22%)/lower (22%) gastrointestinal, and liver (10%) involvement. The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively). The addition of ECP to steroids may result in higher GVHD response as initial therapy for AGVHD, especially for patients with skin-only involvement.
The BCR::ABL1 tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with chronic myeloid leukemia (CML). After failing second‐generation TKI (2G‐TKI), the optimal third‐line ...therapy in chronic phase CML (CML‐CP) is not well established. We analyzed 354 patients with CML‐CP treated with a third‐line BCR::ABL1 TKI at our institution, and in the PACE and OPTIC trials, and evaluated the outcome after alternate 2G‐TKIs or ponatinib. We performed a propensity score matching analysis to compare outcomes and multivariate analysis to identify variables associated with survival. One hundred seventy‐three (49%) patients received 2G‐TKIs and 181 (51%) ponatinib. Patients in the ponatinib group had more cardiovascular risk factors (34% versus 19%) and higher disease burden (BCR::ABL1 transcript levels >1%, 165/175 94% versus 75/135 55%; p < .001) compared with the 2G‐TKI group. Among the 173 evaluable patients treated with ponatinib, 89 (52%) achieved 2 + −log reduction of baseline transcripts (20% 2‐log reduction and 32% 3 + −log reduction). Among the 128 evaluable patients treated with 2G‐TKIs, 44 (34%) achieved 2 + −log reduction of baseline transcripts (13% 2‐log reduction and 21% 3 + −log reduction). With a median follow‐up of 46 months, the 3‐year progression‐free survival was 59% (60% before matching) with 2G‐TKI and 83% (81% before matching) with ponatinib (p < .001). The 3‐year survival was 83% (81% before matching) with 2G‐TKI and 87% (89% before matching) with ponatinib (p = .03). By multivariate analysis, third‐line therapy with ponatinib was the only independent factor associated with better survival (p = .003). In conclusion, ponatinib is an optimal treatment for patients with CML‐CP failing two prior TKIs.
Third‐line therapy with tyrosine kinase inhibitors (TKIs) in 354 patients with chronic myeloid leukemia in chronic phase.
BACKGROUND
The outcome of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. The combination of inotuzumab with low‐intensity mini–hyper‐CVD (mini‐hyper‐CVD; ...cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 × 4 doses) chemotherapy has shown encouraging results. The sequential addition of blinatumomab might improve outcome in patients with R/R ALL.
METHODS
We used lower intensity chemotherapy, mini‐hyper‐CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) compared to conventional hyper‐CVAD.
RESULTS
Ninety‐six patients with a median age of 37 years (range, 18‐87 years) were treated. Overall, 77 patients (80%) responded, 55 (57%) of whom achieved complete response. The overall measurable residual disease negativity rate among responders was 83%. Forty‐four (46%) patients underwent later allogeneic stem cell transplantation. Veno‐occlusive disease of any grade occurred in 10 (10%) patients. The rates were 13% with the original schedule and 3% with the use of lower‐dose inotuzumab and sequential blinatumomab. With a median follow‐up of 36 months, the median overall survival (OS) was 13.4 months, with 3‐year OS rates of 33%. The 3‐year OS rate for patients with CD22 expression ≥70% and without adverse cytogenetics (KMT2A rearrangements, low hypodiploidy/near triploidy) was 55%.
CONCLUSION
The combination of inotuzumab and low‐intensity mini‐hyper‐CVD chemotherapy with or without blinatumomab shows sustained efficacy in patients with R/R ALL.
Low‐intensity chemo‐immunotherapy is safe and highly effective in patients with relapsed/refractory acute lymphoblastic leukemia. Reduced and weekly fractionated inotuzumab with sequential blinatumomab and selection of the least hepatotoxic preparative regimens can reduce toxicities and veno‐occlusive disease rates and may further improve outcomes.
Background
The outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus ofatumumab hyper‐CVAD + ofatumumab (hyper‐CVAD + ofatumumab) has not been compared with ...the outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus ofatumumab hyper‐CVAD plus rituximab (hyper‐CVAD + Rituximab) in Philadelphia chromosome–negative acute lymphoblastic leukemia (ALL) in a randomized clinical trial.
Methods
The authors compared the outcomes of 69 patients treated with hyper‐CVAD + ofatumumab and 95 historical‐control patients treated with hyper‐CVAD + Rituximab. Historical‐control patients were treated with hyper‐CVAD + Rituximab if they had CD20 expression ≥ 20%. Ofatumumab (day 1 of course 1, 300 mg intravenously; subsequent doses, 2000 mg intravenously) was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of 8 doses. A propensity score analysis with inverse probability of treatment weighting (IPTW) was performed to adjust for baseline covariates between groups.
Results
The median event‐free survival with stem cell transplantation (SCT) censoring was 33 and 65 months with hyper‐CVAD + Rituximab and hyper‐CVAD + ofatumumab, respectively (crude P = .064; IPTW P = .054). The median overall survival with SCT censoring was 52 months and not reached, respectively (crude P = .087; IPTW P = .097).
Conclusions
Hyper‐CVAD + ofatumumab was associated with better outcomes than hyper‐CVAD + Rituximab among patients with newly diagnosed Philadelphia chromosome–negative ALL.
The combination of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD) with ofatumumab results in better outcomes than hyper‐CVAD with rituximab in patients with newly diagnosed Philadelphia chromosome–negative acute lymphoblastic leukemia. Ofatumumab may be an optimal anti‐CD20 monoclonal antibody in this setting.
Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive hematological malignancy; however, some patients achieve durable remission with allogeneic hematopoietic cell transplantation ...(allo-HCT). We report on all 17 patients with BPDCN who underwent allo-HCT at our center between 2000 and 2020. The median age was 39 (18-67) years. All (n = 16, 94%), except one patient, had systemic disease involving bone marrow and/or other organs. Ten patients (59%) were in first complete remission (CR1) at allo-HCT. The donor source was matched related or unrelated in ten (59%) and alternate donor in seven (41%) patients. Five (31%) patients developed acute graft-versus-host disease (GVHD), all grade I-II. The cumulative incidence (CI) of chronic GVHD at five-year was 34%. The CI of non-relapse mortality at one-year was 29%. Progression-free survival (PFS) rates at two-year and five-year were 49% (95% CI = 22-71%) and 39% (95% CI = 14-64%), respectively. The two-year and five-year overall survival (OS) rates were 65% (95% CI = 38-82%) and 40% (95% CI = 12-68%), respectively. The five-year rate for both PFS and OS was 80% in CR1 patients versus 0% in patients not in CR1. In conclusion, allo-HCT provides long-lasting remissions in BPDCN patients, particularly when performed in CR1.
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