Lower intensity therapy with cladribine/low dose cytarabine/venetoclax in older patients with acute myeloid leukemia compares favorably with intensive chemotherapy among patients undergoing allogeneic stem cell transplantation.

BACKGROUND: Allogeneic stem cell transplantation (SCT) remains the best consolidative modality in most patients with acute myeloid leukemia (AML). Along with factors directly pertaining to SCT, pretransplantation disease control, performance status, and prior treatment-related complications are important factors that affect posttransplantation survival outcomes. METHODS: The authors compared the survival outcomes of patients ≥60 years of age treated on the phase 2 clinical trial of venetoclax (Ven) added to cladribine (CLAD) and low dose cytarabine (LDAC) alternating with azacitidine (CLAD/LDAC/Ven arm) (NCT03586609) who underwent allogeneic SCT in first remission to a retrospective cohort of patients ≥60 years of age who underwent SCT after intensive chemotherapy. Intensive chemotherapy was defined as the use of cytarabine >1 g/m2 and anthracyclines during induction/consolidation. RESULTS: Thirty-five patients at median age of 68 years in the CLAD/LDAC/Ven arm were compared to 42 patients at a median age of 62 years in the intensive therapy arm. The 2-year relapse-free survival was superior with CLAD/LDAC/Ven versus intensive chemotherapy (88% vs. 65%; p = .03) whereas the 2-year overall survival (OS) was comparable (84% vs. 70%; p = .14). On a competing event analysis, the 2-year cumulative incidence of relapse (CIR) was significantly lower with CLAD/LDAC/Ven versus intensive chemotherapy (2.9% vs. 17.2%, Gray's p = .049) whereas nonrelapse mortality was comparable (16.2% vs. 17.1%; p = .486). CONCLUSION: In conclusion, treatment with CLAD/LDAC/Ven was associated with favorable outcomes in older patients who underwent subsequent allogeneic SCT. The OS was comparable to that with intensive chemotherapy followed by allogeneic SCT, but the CIR rate was significantly lower.

Blinatumomab maintenance after allogeneic hematopoietic cell transplantation for B-lineage acute lymphoblastic leukemia.

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute graft-versus-host disease (GVHD) grades 2 to 4 and 3 to 4 were 33% and 5%, respectively; 2 cases of mild (10%) and 1 case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) rates were 85%, 71%, and 0%, respectively. In a matched analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab's efficacy. Correlative studies of baseline and posttreatment samples identified patients with specific T-cell profiles as "responders" or "nonresponders" to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Nonresponders were T-cell deficient and expressed more inhibitory checkpoint molecules, including T-cell immunoglobulin and mucin domain 3 (TIM3). We found that blinatumomab postallogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment. This paper is posted on ClinicalTrials.gov, study ID: NCT02807883.

Eltrombopag improves platelet engraftment after haploidentical bone marrow transplantation: Results of a Phase II study.

Slow platelet recovery frequently occurs after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with bone marrow graft and post-transplant cyclophosphamide (PCy)-based graft-versus-host disease (GVHD) prophylaxis. Improved platelet recovery may reduce the need for transfusions and improve outcomes. We investigated the safety and efficacy of eltrombopag, a thrombopoietin receptor agonist, at enhancing platelet recovery post-haplo-HSCT. The prospective study included patients ≥18 years of age who received haplo-HSCT with bone marrow graft and PCy. Patients received eltrombopag 300 mg/day starting on Day +5. The primary objective was to estimate platelet engraftment (>50 000/µL by Day 60). In a post hoc analysis, they were compared to a contemporary matched control group who did not receive eltrombopag. One hundred ten patients were included in the analysis (30 eltrombopag and 80 control). Seventy-three percent and 50% of patients in the eltrombopag group and control group, respectively, attained >50 000/µL platelet count by Day 60 (p = .043). No eltrombopag-related grade ≥4 adverse events were observed. Median time to platelet recovery (>20 000/µL) was 29 days with eltrombopag and 31 days for controls (p = .022), while its cumulative incidence was 90% (95% confidence interval [CI]: 78%-100%) with eltrombopag versus 67.5% (95% CI: 57%-78%) for controls (p = .014). Number of platelet transfusions received, overall survival, progression-free survival, GVHD rate, relapse rate, and non-relapse mortality were similar between groups. Overall, eltrombopag is safe and improves platelet recovery in patients undergoing haplo-HSCT with bone marrow graft and PCy.

Safety and long-term survival results of the addition of inotuzumab ozogamicin to the conditioning regimen of allogeneic stem cell transplantation: A single-center phase 1,2 trial.

Here we report on the first prospective study evaluating the safety and long-term survival when an escalating dose of inotuzumab ozogamicin (INO) (0.6, 1.2, or 1.8 mg/m2 on day 13) was added to one alkylator-containing conditioning regimen in patients with relapsed CD22 (+) lymphoid malignancies who were candidates for hematopoietic stem cell transplantation (HSCT). Twenty-six patients were enrolled. Six (23%) of these patients entered the phase 1 study: four were treated at an INO dose of 0.6 mg/m2 and two at dose of 1.2 mg/m2. None of these patients experienced dose-limiting toxicities. The remaining 20 (77%) patients entered the phase 2 part of the study at the maximum dose of 1.8 mg/m2. One patient developed VOD; this patient had received nivolumab immediately before HSCT while simultaneously experiencing hyperacute graft-vs-host disease (GVHD). Treatment-related mortality (TRM) at 5 years was 12%. With a median follow-up of 48.7 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 84% and 80%, respectively. Compared with a historical cohort who received same conditioning for HSCT but without INO (n = 56), the INO group showed no significant differences in incidence of liver toxicity, engraftment time, TRM, or risk of acute GVHD. Patients with lymphoma who received INO had a trend for a better 5-year OS (93% versus 68%) and PFS (93% versus 58%) than those in the control group. In conclusion, our results showed that INO is safe with no increased risk of VOD when combined with one alkylator-containing regimen of HSCT.

Characteristics and outcomes of children, adolescents and young adults with relapsed/refractory non-hodgkin lymphoma undergoing autologous stem cell transplant.

BACKGROUND: There is paucity of data regarding outcomes of children, adolescents and young adults (CAYA) patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT). METHODS: Patients aged 0-39 years undergoing first ASCT for NHL at MD Anderson Cancer Center between 2000 and 2020 were analyzed. RESULTS: Two hundred twenty-one patients were included in the analysis, 129 (58%) were male and the median age was 32 (range 6-39) years. The most common histological subtypes were diffuse large B cell lymphoma (DLBCL) (44%), T-NHL (19%) and primary mediastinal B-Cell lymphoma (PMBCL) (19%). Younger patients (age ≤ 25) had lower incidence of DLBCL and higher incidence of PMBCL and T-NHL compared to older patients (age > 25) (P = 0.02). None of the younger patients had double hit (DH)/double expressor (DE) DLBCL, compared to 14 patients in the older age group (18%, P = 0.07). Considering the three main aggressive NHL subtypes (DLBCL, PMBCL and T-NHL), younger patients had numerically better 15-year post-transplant progression free survival (PFS) (67% vs. 54%) and overall survival (OS) (71% vs. 62%) compared to older patients, yet these differences did not reach statistical significance (P = 0.19 and P = 0.24, respectively). In multivariate analysis, not achieving a CR prior to ASCT was independently predictive of worse PFS [partial remission (PR) (HR, 3.9); stable disease (SD) (HR, 18.0), P = 0.03] and of worse OS [PR (HR, 4.2), SD (HR, 6.5) and progressive disease (HR, 4.7), P < 0.0001]. DH/DE status was an independent adverse predictor of PFS in multivariate analysis (HR 5.8, p = 0.03). Ten patients (4.5%) (all aged > 25 years) developed second primary malignancies (SPM), at a median of 34.4 (range, 1.0-196.6) months after ASCT, and SPM was the cause of death in five (50%) of them. CONCLUSIONS: CAYA NHL patients aged ≤ 25 years who received ASCT presented a distinct NHL histology as compared to older CAYA patients, and none in this younger age group had DH/DE DLBCL. We observed a trend towards improved PFS and OS in younger patients. Disease status at ASCT was predictive of both PFS and OS. DH/DE status was an adverse predictor of PFS.

Younger haploidentical donor versus older matched unrelated donor for patients with AML/MDS.

Optimal donor selection is fundamental to successful allogeneic hematopoietic cell transplantation (HCT), and donor age influences survival after both matched unrelated donor (MUD) and haploidentical donor HCT. Though recent studies have shown similar outcomes between MUD and haploidentical HCT, it is unknown if outcomes differ following HCT with younger haploidentical donors compared to HCT with older MUDs. Therefore, we performed a retrospective analysis comparing outcomes of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients who underwent HCT with younger (≤35 years) haploidentical donors (n = 494) or older (>35 years) MUDs (n = 1005). Patients in the haploidentical and MUD groups received post-transplant cyclophosphamide (PTCy) and conventional graft-versus-host-disease (GVHD) prophylaxis, respectively. In multivariate analysis, use of younger haploidentical donors was associated with improved overall survival (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.69-0.95, p = .01) and lower rates of grade II-IV acute GVHD (HR 0.64, 95% CI 0.53-0.77, p < .001), grade III-IV acute GVHD (HR 0.37, 95% CI 0.25-0.53, p < .001), and chronic GVHD (HR 0.49, 95% CI 0.40-0.60, p < .001). Relapse rates were similar among those who received myeloablative conditioning but were higher in patients of the younger haploidentical group who received reduced intensity conditioning (HR 1.49, 95%CI 1.18-1.88, p = .001). The younger haploidentical group had significantly lower non-relapse mortality ≥3 months post-HCT (HR 0.59, 95% CI 0.38-0.90, p = .02). Our data support the use of younger haploidentical donors with PTCy over older MUDs with conventional prophylaxis in patients with MDS or AML. Further studies on the importance of donor age in haploidentical and MUD HCT with PTCy prophylaxis are warranted.

Evolving trends and outcomes in older patients with acute myeloid leukemia including allogeneic stem cell transplantation.

Outcomes in older patients with acute myeloid leukemia (AML) have historically been poor. Given advances in low-intensity therapy (LIT) and stem cell transplantation (SCT), we performed a retrospective single-center study to evaluate the contemporary outcomes of this population. We reviewed all patients ≥60 years with newly diagnosed AML between 2012 and 2021 and analyzed treatment and SCT-related trends and outcomes. We identified 1073 patients with a median age of 71 years. Adverse clinical and cytomolecular findings were frequent within this cohort. In total, 16% of patients were treated with intensive chemotherapy, 51% with LIT alone, and 32% with LIT plus venetoclax. The composite complete remission rate with LIT plus venetoclax was 72%, which was higher than with LIT alone (48%, p < .0001) and comparable to intensive chemotherapy (74%, p = .6). The median overall survival (OS) with intensive chemotherapy, LIT, and LIT plus venetoclax was 20.1, 8.9, and 12.1 months, respectively. 18% of patients received SCT. SCT rates were 37%, 10%, and 22% in patients treated with intensive chemotherapy, LIT, and LIT plus venetoclax, respectively. The 2-year OS, relapse-free survival (RFS), cumulative incidence (CI) of relapse, and CI of treatment-related mortality with frontline SCT (n = 139) were 59%, 52%, 27%, and 22%, respectively. By landmark analysis, patients undergoing frontline SCT had superior OS (median 39.6 vs. 21.4 months, p < .0001) and RFS (30.9 vs. 12.1 months, p < .0001) compared with responding patients who did not. Outcomes in older patients with AML are improving with more effective LIT. Measures should be pursued to increase access to SCT in older patients.

Is there an optimal conditioning for older patients with AML receiving allogeneic hematopoietic cell transplantation?

The optimal conditioning regimen for older patients with acute myeloid leukemia (AML) remains unclear. In this study, we compared outcomes of AML patients >60 years of age undergoing allogenic hematopoietic stem cell transplantation at our institution. All 404 consecutively treated patients received 1 of the following conditioning regimens: (1) fludarabine+melphalan 100 mg/m2 (FM100), (2) fludarabine+melphalan 140 mg/m2 (FM140), (3) fludarabine+IV busulfan AUC ≥ 5000/d × 4 d (Bu≥20000), and (4) fludarabine+IV busulfan AUC 4000/d × 4 d (Bu16000). A propensity score analysis (PSA) was used to compare outcomes between these 4 groups. Among the 4 conditioning regimens, the FM100 group had a significantly better long-term survival with 5-year progression-free survival of 49% vs 30%, 34%, and 23%, respectively. The benefit of the FM100 regimen resulted primarily from the lower nonrelapse mortality associated with this regimen, an effect more pronounced in patients with lower performance status. The PSA confirmed that FM100 was associated with better posttransplantation survival, whereas no significant differences were seen between the other regimen groups. In summary, older patients with AML benefited from a reduced-intensity conditioning regimen with lower melphalan doses (FM100), which was associated with better survival, even though it was primarily used in patients who could not receive a more intense conditioning regimen.

Improved outcomes of high-risk relapsed Hodgkin lymphoma patients after high-dose chemotherapy: a 15-year analysis.

High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment for chemosensitive relapsed classical Hodgkin lymphoma, although outcomes of high-risk relapse (HRR) patients remain suboptimal. We retrospectively analyzed all HRR classical Hodgkin lymphoma patients treated with HDC/ASCT at our institution between 01/01/2005 and 12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring more than one salvage line, or positron emission tomography (PET)-positive disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (n=146), busulphan/melphalan (BuMel) (n=38), gemcitabine( Gem)/BuMel (n=189) and vorinostat/Gem/BuMel (n=128). The Gem/BuMel and vorinostat/Gem/BuMel cohorts had more HRR criteria and more patients with PET-positive disease at ASCT. Treatment with brentuximab vedotin (BV) or anti-PD1 prior to ASCT, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). The median follow-up is 50 months (range, 6-186). Outcomes improved over time, with 2-year progressionfree survival (PFS)/overall survival (OS) rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016- 2019) (P<0.0001). Five-year PFS/OS rates were 72%/87% after vorinostat/ GemBuMel, 55%/75% after GemBuMel, 45%/61% after BEAM, and 39%/57% after BuMel (PFS: P=0.0003; OS: P<0.0001). These differences persisted within the PET-negative and PET-positive subgroups. Prior BV and vorinostat/GemBuMel were independent predictors of more favorable outcome, whereas primary refractory disease, ≥2 salvage lines, bulky relapse, B symptoms and PET-positivity at ASCT correlated independently with unfavorable outcomes. In conclusion, post-HDC/ASCT outcomes of patients with HRR classic Hodgkin lymphoma have improved over the last 15 years. Pre-ASCT BV treatment and optimized synergistic HDC (vorinostat/GemBuMel) were associated with this improvement.

Clinical outcomes and impact of therapeutic intervention in patients with acute myeloid leukemia who experience measurable residual disease (MRD) recurrence following MRD-negative remission.

Recurrence of MRD in AML is associated with imminent relapse unless intervened upon. Change in chemotherapy regimen and/or immediate transplant improve outcomes.

Value and pitfalls of assessing bone marrow morphologic findings to predict response in patients with myelofibrosis who undergo hematopoietic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with myelofibrosis (MF). Bone marrow (BM) morphologic evaluation of myelofibrosis following allo-HSCT is known to be challenging in this context because resolution of morphologic changes is a gradual process. PATIENTS AND METHODS: We compared BM samples of patients with myelofibrosis who underwent first allo-HSCT and achieved molecular remission by day 100 with BM samples of patients who continued to have persistent molecular evidence of disease following allo-HSCT. RESULTS: The study group included 29 patients: 17 primary MF, 7 post-polycythemia vera (PV) MF, and 5 post-essential thrombocythemia (ET) MF. In this cohort there were 18 JAK2 p.V617F, 8 CALR; 1 MPL, and 2 patients had concurrent JAK2 p.V617F and MPL mutations. The control group included 5 patients with primary MF, one with post-PV MF, one with post-ET MF (5 JAK2 p.V617F; 2 CALR). Following allo-HSCT, both groups showed reduction in BM cellularity and number of megakaryocytes. The study cohort also less commonly had dense megakaryocyte clusters and endosteal located megakaryocytes and showed less fibrosis. There was no statistical difference in BM cellularity, presence of erythroid islands, degree of osteosclerosis, or megakaryocyte number, size, nuclear lobation, presence of clusters or intrasinusoidal location. CONCLUSIONS: Following allo-HSCT at 100 days, morphologic evaluation of BM in patients with MF cannot reliably predict persistence versus clearance of molecular evidence of MF. Disappearance of BM MF, dense megakaryocyte clusters, and endosteal localization of megakaryocytes are suggestive of disease response.

Post-Transplant Cyclophosphamide after Matched Sibling and Unrelated Donor Hematopoietic Stem Cell Transplantation in Pediatric Patients with Acute Myeloid Leukemia.

Non-relapse mortality due to GVHD and infections represents a major source of morbidity and mortality in pediatric HSCT recipients. Post-transplant cyclophosphamide (PTCy) has emerged as an effective and safe GVHD prophylaxis strategy, with improved GVHD and relapse-free survival in matched (related and unrelated) and mismatched haploidentical HSCT adult recipients. However, there are no published data in pediatric patients with acute myeloid leukemia who received matched-donor HSCT with PTCy. We demonstrate, in this case series, that the use of PTCy in this population is potentially safe, effective in preventing acute GVHD, does not impair engraftment, is associated with reduced non-relapse mortality, and does not hinder immune reconstitution post HSCT.

Fractionated busulfan myeloablative conditioning improves survival in older patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: A myeloablative conditioning regimen can be safely given to older patients and those with comorbidities without increasing nonrelapse mortality (NRM) by fractionating the dose of intravenous busulfan. How this approach compares in efficacy with traditional, nonfractionated, lower dose regimens is unknown. METHODS: Outcomes were compared in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received either myeloablative, fractionated busulfan (f-Bu) dosed to achieve an area under the curve of 20,000 µmol per minute (f-Bu20K) over 2 weeks (n = 84) or a standard, nonfractionated, lower busulfan dose regimen of 16,000 µmol per minute (Bu16K) over 4 days (n = 78). Both groups also received fludarabine 40 mg/m2 intravenously for 4 days. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Patients in the Bu16K group who had unrelated donors also received antithymocyte globulin. The primary endpoint was progression-free survival. RESULTS: Roughly one-half of the patients were aged >65 years, approximately 40% had poor-risk cytogenetics, approximately 40% of those with AML were not in complete remission, and approximately 40% had a comorbidity index >3. At 2 years, progression-free survival was significantly improved in the f-Bu20K group compared with the Bu16K group (45% vs 24%, respectively; hazard ratio [HR], 0.6; 95% CI, 0.4-0.8; P = .004). This was because of a significant reduction in progression (34% vs 59%, respectively; HR, 0.5; 95% CI, 0.3-0.8; P = .003) without any increase in NRM (21% vs 15%, respectively; HR, 1.4; 95% CI, 0.7-3; P = .3), which resulted in improved overall survival (51% vs 31%, respectively; HR, 0.6; 95% CI, 0.3-0.9; P = .01). CONCLUSIONS: A myeloablative, fractionated busulfan regimen reduces relapse and improves survival without increasing NRM in older patients with AML and myelodysplastic syndrome.

Outcomes in patients with newly diagnosed TP53-mutated acute myeloid leukemia with or without venetoclax-based therapy.

BACKGROUND: Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has become the standard of care for patients aged >75 years and for those not eligible for intensive chemotherapy who have newly diagnosed acute myeloid leukemia (AML). The benefit of VEN-based therapy in patients who have newly diagnosed AML with mutations in the TP53 gene (TP53mut ) over standard therapy is undefined. METHODS: In this single-institutional, retrospective analysis, the authors assessed the clinical outcomes of 238 patients with newly diagnosed TP53mut AML and compared the clinical characteristics, response to different therapies, and outcomes of those who received VEN-based (n = 58) and non-VEN-based (n = 180) regimens. RESULTS: Patients who received VEN-based regimens were older (aged >65 years: 81% vs 65%; P = .02) and had higher response rates (complete remission, 43% vs 32%; P = .06) than those who received non-VEN-based regimens. Compared with patients who received non-VEN-based regimens, no difference in overall survival (median, 6.6 vs 5.7 months; P = .4) or relapse-free survival (median, 4.7 vs 3.5 months; P = .43) was observed in those who received VEN-based regimens, regardless of age or intensity of treatment. CONCLUSIONS: The addition of VEN to standard treatment regimens did not improve outcomes in younger or older patients who had TP53mut AML. These data highlight the need for novel therapies beyond VEN to improve the outcome of patients with TP53mut AML.

Long-term results of low-intensity chemotherapy with clofarabine or cladribine combined with low-dose cytarabine alternating with decitabine in older patients with newly diagnosed acute myeloid leukemia.

The treatment of older patients with newly diagnosed acute myeloid leukemia (AML) using intensive chemotherapy is associated with treatment intolerance and poor survival. We evaluated two new lower-intensity regimens with clofarabine (n = 119) or cladribine (n = 129) combined with low-dose cytarabine (LDAC) alternating with decitabine. We reviewed response rates by subgroup and long term outcomes of 248 patients with newly diagnosed non core-binding-factor AML treated on two clinical trials investigating double nucleoside-analogue therapy (DNT) alternating with HMA from October, 2008 to April, 2018. Of 248 patients with a median age of 69 years (range, 49-85 years), 102 patients (41%) were ≥ 70 years, and 108 (44%) had adverse karyotype. Overall, 164 patients (66%) responded: 147 (59%) complete remission (CR) and 17 (7%) CR with incomplete count recovery (CRi). With a median follow up of 60 months, median relapse-free and overall survival (OS) were 10.8 and 12.5 months, respectively. The 2-year OS was 29%. Among patients with normal karyotype, the CR/CRi rate was 79% and the median OS 19.9 months. High response rates and OS were observed in patients with mutations in NPM1, FLT3, IDH2, and RUNX1. The 4- and 8-week mortality rates were 2% and 11%, respectively. The backbone of clofarabine or cladribine and LDAC alternating with decitabine was effective and safe for the treatment of older patients with newly diagnosed AML. Incorporating targeted therapies could extend the efficacy of this approach and provide more curative therapeutic options in this AML population.

Cytogenetics and Blast Count Determine Transplant Outcomes in Patients with Active Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) patients not in remission and beyond first or second complete remission are considered allogeneic stem cell transplant (SCT) candidates. We present 361 patients who underwent SCT from matched related or unrelated donors between 2005 and 2013. The purpose was to identify a subgroup of patients with active disease at the time of transplant that benefit. Cox proportional hazards regression analysis was used for univariate and multivariate analyses to predict overall survival (OS). Variables considered were age, sex, SWOG cytogenetic risk group, bone marrow (BM) and peripheral blood (PB) blast percentage, regimen intensity, and type of AML. At a median of 26 months after transplantation, OS, progression-free survival (PFS), non-relapse mortality, and relapse rates were 26, 24, 23, and 48%, respectively. In a univariate analysis, risk cytogenetics (p < 0.001) and BM blasts >4% (p = 0.006) or any blasts in PB (p < 0.001) indicated worse OS. In a multivariate analysis, patients with <5% BM blasts or absence of circulating blasts and good or intermediate risk cytogenetics had significantly superior OS (46%), PFS (44%), and disease progression at 3 years. Based on these findings, patients not in remission with good or intermediate risk cytogenetics and low blast counts should be considered for SCT.

Optimizing the Conditioning Regimen for Hematopoietic Cell Transplant in Myelofibrosis: Long-Term Results of a Prospective Phase II Clinical Trial.

Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear. We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m2/day on days -3 and -2 ("low dose"); 31 patients received high-dose conditioning, either 100 mg/m2/day (days -5 to -2; n = 4) or pharmacokinetic-guided area under the curve of 4000 µmol/min (days -5 to -2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM). Median age was 58 years (interquartile range [IQR], 53-63). Dynamic international prognostic scoring system-plus was intermediate (n = 28) or high (n = 18). Donors were related (n = 19) or unrelated (n = 27). Cumulative incidence of NRM was 9.7% (95% confidence interval [CI], 0-20.3) at day 100 and at 3 years in the high-dose group and 0% in the low-dose group at day 100, which increased to 20% (95% CI, 0-41.9) at 3 years. With a median follow-up of 5.1 years (IQR, 3.8-6), 3-year relapse was 32.3% (95% CI, 15.4-49.1) in high dose versus 53.3% (95% CI, 26.6-80.1) in low dose. Event-free survival was 58% (95% CI, 43-78) versus 27% (95% CI, 12-62), and overall survival was 74% (95% CI, 60-91) versus 60% (95% CI, 40-91). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio, .44; 95% CI, .18-1.07; P = .07), with no impact on NRM. Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM.

Novel Disease Risk Model for Patients with Acute Myeloid Leukemia Receiving Allogeneic Hematopoietic Cell Transplantation.

Molecular data and minimal residual disease (MRD) have been shown to influence outcomes in acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic cell transplantation (AHCT). Here we developed and validated a novel AML-specific disease risk group (AML-DRG) and revised our previously developed hematopoietic cell transplant-composite risk (HCT-CR) model by incorporating molecular data and MRD status to predict outcomes of patients with AML. The study included 1414 consecutively treated adult AML patients who received a first AHCT. Patients were randomly assigned into training (n = 944) and validation (n = 470) sets. To develop the AML-DRG model, the coefficient of all significant AML-related variables in multivariable Cox regression analysis in a training dataset was converted into scores, whereas the AML-HCT-CR was the sum of disease-related factors assessed by the AML-DRG model with the addition of weighted scores from patient-related factors. The AML-DRG was developed by assigning the following scores: 1 point to secondary AML, 1 point to the European LeukaemiaNet adverse genetic risk, 2 points to complete remission with MRD positive/unknown, and 4 points to active disease. These scores were used to generate 3 risk groups of the AML-DRG with significantly different overall survivals. By adding the score for significant patient-related factors (HCT-specific comorbidity index/age), we created 4 risk groups of AML-HCT-CR with distinct survival outcomes. Both the AML-DRG and AML-HCT-CR provided significantly better discriminative capacity compared with the disease risk index, European LeukaemiaNet genetic risk model, and cytogenetic risk model. Prognostic models incorporating molecular data and MRD status allow better stratification and improved survival estimates of AML patients post-transplant.

Age Is a Prognostic Factor for the Overall Survival of Patients with Multiple Myeloma Undergoing Upfront Autologous Hematopoietic Stem Cell Transplantation.

In this retrospective analysis, we evaluated the impact of age on the outcome of patients with multiple myeloma who received an autologous hematopoietic stem cell transplantation (auto-HCT) at our institution. A total of 1128 patients were divided into the older (>70 years; 182 [16%]) and the younger (≤70 years; 946 [84%]) groups. Compared with the younger cohort, older patients had a higher International Staging System (ISS) stage (ISS-II, 57 [31%] versus 215 [23%]; ISS-III, 52 [28%] versus 211 [22%]; P = .01), higher use of reduced-dose melphalan as a conditioning regimen (140 mg/m², 59 [32%] versus 29 [3%]; P < .001), and a higher comorbidity index (median, 3 versus 2; P = .01). Nonrelapse mortality at 1 year after auto-HCT was significantly higher in older patients (7 [4%] versus 9 [1%]; hazard ratio [HR], 4.1; P = .005). Complete remission rates after auto-HCT for the older and the younger groups were 41% and 46%, respectively. With a median follow-up of 52 months, the 5-year progression-free survival (PFS) was 24% (95% confidence interval [CI], 17% to 32%) and 37% (95% CI, 33% to 40%) in the older and younger groups, respectively (HR, 1.3; P = .02). Five-year OS for the older and younger groups was 56% (95% CI, 47% to 64%) and 73% (95% CI, 70% to 76%; P < .001), respectively. Older age emerged as one of the predictors of shorter OS but not PFS in the multivariate classification and regression tree analysis. In conclusion, age ≥70 years was associated with shorter PFS and OS in patients with multiple myeloma who underwent an auto-HCT.

The Role of Donor Lymphocyte Infusion (DLI) in Post-Hematopoietic Cell Transplant (HCT) Relapse for Chronic Myeloid Leukemia (CML) in the Tyrosine Kinase Inhibitor (TKI) Era.

Treatment for relapse of chronic myeloid leukemia (CML) following hematopoietic cell transplantation (HCT) includes tyrosine kinase inhibitors (TKIs) with or without donor lymphocyte infusions (DLIs), but the most effective treatment strategy is unknown. This study was performed through the Center for International Blood and Marrow Transplant Research (CIBMTR) database. We retrospectively reviewed all patients reported to the CIBMTR registry from 2002 to 2014 who underwent HCT for CML and were alive 30 days postrelapse. A total of 215 HCT recipients relapsed and were analyzed in the following groups: (1) TKI alone (n = 128), (2) TKI with DLI (n = 48), and (3) DLI without TKI (n = 39). In multivariate analysis, disease status prior to HCT had a significant effect on overall survival (OS). Patients who received a DLI alone compared with a TKI with a DLI had inferior survival (hazard ratio, 2.28; 95% confidence interval, 1.23 to 4.24; P= .009). Those who received a TKI alone had similar survival compared with those who received a TKI with a DLI (P = .81). These data support that despite use of TKIs pretransplantation, TKI salvage therapy continues to provide significant survival following relapse in patients with CML following HCT. These data do not suggest that adding a DLI to a TKI adds an improvement in OS.