Allogeneic transplantation is not superior to chemotherapy in most patients over 40 years of age with Philadelphia‐negative acute lymphoblastic leukemia in first remission

Wolach, Ofir; Stevenson, Kristen E.; Wadleigh, Martha; DeAngelo, Daniel J.; Steensma, David P.; Ballen, Karen K.; Soiffer, Robert J.; Antin, Joseph H.; Neuberg, Donna; Ho, Vincent T.; Stone, Richard

doi:10.1002/ajh.24410

Cited by 14 publications

(8 citation statements)

References 35 publications

(56 reference statements)

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“…This broad indication for HSCT may have contributed to transplantationrelated mortality; nevertheless, mortality is in line with reports of HSCT in standard of care ranging between 20% to 30%. [31][32][33][34][35] The proportion of patients not undergoing transplantation was small, and the study was neither planned nor powered to assess the impact of HSCT after blinatumomab treatment.…”

Section: Discussionmentioning

confidence: 99%

Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia

Gökbuget

Dombret

Bonifacio

et al. 2018

Blood

581

461

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Approximately 30% to 50% of adults with acute lymphoblastic leukemia (ALL) in hematologic complete remission after multiagent therapy exhibit minimal residual disease (MRD) by reverse transcriptase-polymerase chain reaction or flow cytometry. MRD is the strongest predictor of relapse in ALL. In this open-label, single-arm study, adults with B-cell precursor ALL in hematologic complete remission with MRD (≥10) received blinatumomab 15 µg/m per day by continuous IV infusion for up to 4 cycles. Patients could undergo allogeneic hematopoietic stem-cell transplantation any time after cycle 1. The primary end point was complete MRD response status after 1 cycle of blinatumomab. One hundred sixteen patients received blinatumomab. Eighty-eight (78%) of 113 evaluable patients achieved a complete MRD response. In the subgroup of 110 patients with Ph-negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In landmark analyses, complete MRD responders had longer RFS (23.6 vs 5.7 months; = .002) and OS (38.9 vs 12.5 months; = .002) compared with MRD nonresponders. Adverse events were consistent with previous studies of blinatumomab. Twelve (10%) and 3 patients (3%) had grade 3 or 4 neurologic events, respectively. Four patients (3%) had cytokine release syndrome grade 1, n = 2; grade 3, n = 2), all during cycle 1. After treatment with blinatumomab in a population of patients with MRD-positive B-cell precursor ALL, a majority achieved a complete MRD response, which was associated with significantly longer RFS and OS compared with MRD nonresponders. This study is registered at www.clinicaltrials.gov as #NCT01207388.

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Section: Discussionmentioning

confidence: 99%

Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia

Gökbuget

Dombret

Bonifacio

et al. 2018

Blood

581

461

View full text Add to dashboard Cite

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“…Importantly, the generally low NRM rate for all patients translates into an equal survival rate for younger vs. older patients (Fig 3). This observation is critical to studies that don’t show benefit to transplant versus chemotherapy due to higher NRM(2, 44). …”

Section: Discussionmentioning

confidence: 99%

Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results

Kebriaei

Bassett

Lyons

et al. 2017

Biology of Blood and Marrow Transplantation

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We investigated the long-term safety and disease-control data obtained with intravenous busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (SCT). 107 patients with median age 38 years (range 19–64 years) received a matched sibling (n=52), or matched unrelated donor transplant (n=55) for ALL in first complete remission (n=62), second complete remission (n=28), or more advanced disease (n=17). Nearly half of the patients had high-risk cytogenetic profiles as defined by the presence of t(9;22) (n=34), t(4;11) (n=4), or complex cytogenetics (n=7). Clo 40 mg/m2 was given once daily, each dose followed by pharmacokinetically-dosed Bu infused over three hours daily for 4 days, followed by hematopoietic cell infusion after two rest days. The Bu dose was based upon the drug clearance determined by a test Bu dose, 32 mg/m2, given 48 hours prior to the high dose regimen. The target daily area under the curve (AUC) was 5,500 microMol-min for patients less than 60 years of age and 4000 microMol-min for patients older than 59 years of age. With a median follow-up of 3.3 years among surviving patients (1–5.8 years), the 2-year progression-free survival (PFS) rates for patients transplanted in CR1, CR2, or more advanced disease were 62%, 34%, and 35%, respectively. The regimen was well tolerated with non-relapse mortality (NRM) rates of 10% and 31% and at 100 days and 2 years, respectively. The incidence of grades II–IV and III–IV acute graft versus host disease (GVHD) were 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) rates for patients transplanted in CR1, CR2, or more advanced disease were 70%, 57%, and 35%, respectively. Among 11 patients older than 59 years treated with reduced dose Bu in CR1 (n=7) or CR2 (n=4), 4 remain alive and disease-free with a median follow up of 2.6 years (2–4.7 years). Only the presence of MRD at time of transplant was associated with significantly worse PFS and OS on multivariate analysis. The Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. Overall survival and NRM rates compare favorably with traditional myeloablative TBI-based conditioning regimens.

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“…Therapy‐related ALL is an increasingly reported entity that in ‘real‐life’ cohorts comprise 7–10% of adult ALL cases. Although not strictly controlled for, this entity seems to be associated with HR features and poor survival (Abdulwahab et al , ; Ganzel et al , ; Wolach et al , ).…”

Section: Patient Risk Stratification – From Traditional Risk Factors mentioning

confidence: 99%

“…No difference in outcome was demonstrated for patients undergoing HSCT as compared to chemotherapy‐only treated patients (Fathi et al , ). Another retrospective analysis of patients aged >40 years showed no survival advantage for patients transplanted in remission as compared with those treated with chemotherapy‐only (40% vs. 46%) (Wolach et al , ). Although less studied in older adults, MRD remains a powerful means for assessing response and relapse risk and should be investigated prospectively as a tool for post‐remission decision analysis.…”

Section: Choosing the Right Approach For The Right Patientmentioning

confidence: 99%

Current challenges and opportunities in treating adult patients with Philadelphia‐negative acute lymphoblastic leukaemia

2017

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Significant advances have been made in recent years in the field of Philadelphia-negative acute lymphoblastic leukaemia (ALL). New insights into the biology and genetics of ALL as well as novel clinical observations and new drugs are changing the way we diagnose, risk-stratify and treat adult patients with ALL. New genetic subtypes and alterations refine risk stratification and uncover new actionable therapeutic targets. The incorporation of more intensive, paediatric and paediatric-inspired approaches for young adults seem to have a positive impact on survival in this population. Minimal residual disease at different time points can assist in tailoring risk-adapted interventions for patients based on individual response. Finally, novel targeted approaches with monoclonal antibodies, immunotherapies and small molecules are moving through clinical development and entering the clinic. The aim of this review is to consolidate the abundance of emerging data and to review and revisit the concepts of risk-stratification, choice of induction and post-remission strategies as well as to discuss and update the approach to specific populations with ALL, such as young adult, elderly/unfit and relapsed/refractory patients with ALL.

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Allogeneic transplantation is not superior to chemotherapy in most patients over 40 years of age with Philadelphia‐negative acute lymphoblastic leukemia in first remission

Cited by 14 publications

References 35 publications

Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia

Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia

Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results

Current challenges and opportunities in treating adult patients with Philadelphia‐negative acute lymphoblastic leukaemia

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