The role of allogeneic transplant for adult Ph+ ALL in CR1 with complete molecular remission: a retrospective analysis

Ghobadi, Armin; Slade, Michael; Kantarjian, Hagop M.; Alvarenga, Julio; Aldoss, Ibrahim; Mohammed, Kahee A.; Jabbour, Elias; Faramand, Rawan; Shah, Bijal; Locke, Frederick L.; Fingrut, Warren; Park, Jae H.; Short, Nicholas J.; Gao, Feng; Uy, Geoffrey L.; Westervelt, Peter; DiPersio, John F.; Champlin, Richard E.; Malki, Monzr M. Al; Ravandi, Farhad; Kebriaei, Partow

doi:10.1182/blood.2022016194

Cited by 36 publications

(29 citation statements)

References 43 publications

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“…also demonstrate that, compared with non‐HCT approaches with modern induction regimens and TKIs, allo‐HSCT in CR1 for patients achieving CMR within 90 days of diagnosis is not associated with an improvement in OS or recurrence‐free survival. This result persisted after adjustment for imbalances in baseline risk factors using traditional multivariable analysis and on propensity score matching 49 …”

Section: Discussionmentioning

confidence: 91%

“…This result persisted after adjustment for imbalances in baseline risk factors using traditional multivariable analysis and on propensity score matching. 49 In addition to the most commonly used real-time quantitative PCR of BCR::ABL1 transcripts, the detection methods of MRD in Ph+ ALL also include multiparameter flow cytometry (MFC) and PCR of immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements. In our meta-analysis, most included studies used reverse transcriptase PCR of BCR::ABL1 to assess MRD, [5][6][7]15,16,31,35,36,41 and only one study applied these three methods to detect MRD in Ph+ ALL, respectively.…”

Section: Publication Biasmentioning

confidence: 99%

“…confirmed no difference in OS rates between allo-HSCT/non-SCT cohorts was driven by an excess of nonrelapse mortality in the allo-HSCT cohort, which was balanced by a decrease in the incidence of relapse. Allo-HSCT was also associated with inferior graft-versus-host disease free-relapse-free survival, which could be interpreted as a surrogate marker for survival with a good quality of life 49. limitations; specifically, confounding by indication is a significant concern for retrospective analyses of transplant versus nontransplant approaches.…”

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confidence: 99%

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Chemotherapy with the use of next‐generation tyrosine kinase inhibitors based on measurable residual disease has the potential to avoid hematopoietic stem cell transplantation in treatment for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia

Xie

Shi

Jiang

et al. 2023

Cancer

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Background Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) as postremission treatment is recommended for Philadelphia‐positive acute lymphoblastic leukemia (Ph+ ALL) in current guidelines. However, comparisons of later generation tyrosine kinase inhibitors (TKIs) plus chemotherapy with allo‐HSCT have yielded similar outcomes. This meta‐analysis was performed to evaluate allo‐HSCT in first complete remission (CR1) versus chemotherapy for adult Ph+ ALL in the TKI era. Methods Pooled assessment of the hematologic and molecular complete response rates was performed after 3‐month TKI treatment. Hazard ratios (HRs) were determined for disease‐free survival (DFS) and overall survival (OS) benefit with allo‐HSCT. The effect of measurable residual disease status on survival benefit was also analyzed. Results Thirty‐nine retrospective and prospective single‐arm cohort studies involving 5054 patients were included. Combined HRs indicated that in the general population, allo‐HSCT favorably influenced DFS and OS. Achieving complete molecular remission (CMR) within 3 months after starting induction was a favorable survival prognostic factor regardless of whether the patient had undergone allo‐HSCT. Among the patients with CMR, survival rates in the nontransplant subgroup were comparable with those in the transplant subgroup, with the estimated 5‐year OS of 64% versus 58% and 5‐year DFS of 58% versus 51%, respectively. The use of next‐generation TKIs results in a higher proportion of patients achieving CMR (ponatinib 82% vs. imatinib 53%), while improving survival in nontransplant patients. Conclusion Our novel findings suggest that combination chemotherapy plus TKIs leads to a comparable survival benefit as with allo‐HSCT for MRD‐negative (CMR) patients. This study provides novel evidence for allo‐HSCT indications for Ph+ ALL in CR1 in the TKI era.

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Section: Discussionmentioning

confidence: 91%

Section: Publication Biasmentioning

confidence: 99%

mentioning

confidence: 99%

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Chemotherapy with the use of next‐generation tyrosine kinase inhibitors based on measurable residual disease has the potential to avoid hematopoietic stem cell transplantation in treatment for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia

Xie

Shi

Jiang

et al. 2023

Cancer

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“…Achievement of CMR is prognostic in Ph+ ALL and has been used as a primary endpoint in several clinical trials 3,17,19–22 . Persistent MRD by RT‐PCR for BCR::ABL1 is also commonly used in clinical practice to identify patients who should be considered for blinatumomab or allogeneic alloSCT 4,23,24 . Our data suggest that persistent BCR::ABL1 should not be used in isolation as a justification for escalation of therapy, as many of these patients have no detectable disease using a highly sensitive NGS‐based MRD assay and have durable remissions and survival.…”

Section: Discussionmentioning

confidence: 92%

Ultrasensitive NGS MRD assessment in Ph+ ALL: Prognostic impact and correlation with RT‐PCR for BCR::ABL1

et al. 2023

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Reverse transcription polymerase chain reaction (RT‐PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL); however, RT‐PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next‐generation sequencing (NGS) MRD assay (sensitivity of 10−6) and its correlation with RT‐PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT‐PCR and NGS, and 31% of patients who achieved NGS MRD negativity were PCR+ at the same timepoint. Among eight patients with long‐term detectable BCR::ABL1 by PCR, six were PCR+/NGS−. These patients generally had stable PCR levels that persisted despite therapeutic interventions, and none subsequently relapsed; in contrast, patients who were PCR+/NGS+ had more variable PCR values that responded to therapeutic intervention. In a separate cohort of prospectively collected clinical samples, 11 of 65 patients (17%) with Ph+ ALL who achieved NGS MRD negativity had detectable BCR::ABL1 by PCR, and none of these patients relapsed. Relapse‐free survival and overall survival were similar in patients who were PCR+/NGS− and PCR−/NGS−, suggesting that PCR for BCR::ABL1 did not provide additional prognostic information in patients who achieved NGS MRD negativity. NGS‐based assessment of MRD is prognostic in Ph+ ALL and identifies patients with low‐level detectable BCR::ABL1 who are unlikely to relapse nor to benefit from therapeutic interventions.

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“…However, a recently published multicenter, retrospective analysis did not show a benefit of allo-HCT in adults with Ph+ ALL who achieved a complete molecular remission within 90 days of treatment initiation. 9 …”

Section: Introductionmentioning

confidence: 99%

CNS Involvement at Initial Diagnosis and Risk of Relapse After Allogeneic HCT for Acute Lymphoblastic Leukemia in First Complete Remission

et al. 2022

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Outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult acute lymphoblastic leukemia (ALL) have improved over time. Studies have shown that total body irradiation (TBI) is the preferable type of myeloablative conditioning (MAC). However, outcomes based on central nervous system (CNS) involvement, namely CNS-positive versus CNS-negative, have not been compared. Here, we evaluated outcomes of 547 patients (CNS-positive = 96, CNS-negative = 451) who were allografted in the first complete remission (CR1) between 2009 and 2019. Primary endpoint was leukemia-free survival (LFS). Median follow-up was not different between the CNS-positive and CNS-negative groups (79 versus 67.2 months, P = 0.58). The CNS-positive group were younger (median age 31.3 versus 39.7 years, P = 0.004) and were allografted more recently (median year 2012 versus 2010, P = 0.003). In both groups, MAC was the preferred approach (82.3% versus 85.6%, P = 0.41). On multivariate analysis, the CNS-positive group had higher incidence of relapse (RI) (hazard ratio [HR] = 1.58 [95% confidence interval (CI) = 1.06-2.35], P = 0.025), but no adverse effect on LFS (HR = 1.38 [95% CI = 0.99-1.92], P = 0.057) or overall survival (OS) (HR = 1.28 [95% CI = 0.89-1.85], P = 0.18). A subgroup multivariate analysis limited to CNS-positive patients showed that a TBI-based MAC regimen resulted in better LFS (HR = 0.43 [95% CI = 0.22-0.83], P = 0.01) and OS (HR = 0.44 [95% CI = 0.21-0.92], P = 0.03) and lower RI (HR = 0.35 [95% CI = 0.15-0.79], P = 0.01). Another subgroup analysis in CNS-negative patients showed that MAC-TBI preparative regimens also showed a lower RI without a benefit in LFS or OS. While a MAC-TBI allo-HCT regimen may not be suitable to all, particularly for older patients with comorbidities, this approach should be considered for patients who are deemed fit and able to tolerate.

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The role of allogeneic transplant for adult Ph+ ALL in CR1 with complete molecular remission: a retrospective analysis

Cited by 36 publications

References 43 publications

Chemotherapy with the use of next‐generation tyrosine kinase inhibitors based on measurable residual disease has the potential to avoid hematopoietic stem cell transplantation in treatment for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia

Chemotherapy with the use of next‐generation tyrosine kinase inhibitors based on measurable residual disease has the potential to avoid hematopoietic stem cell transplantation in treatment for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia

Ultrasensitive NGS MRD assessment in Ph+ ALL: Prognostic impact and correlation with RT‐PCR for BCR::ABL1

CNS Involvement at Initial Diagnosis and Risk of Relapse After Allogeneic HCT for Acute Lymphoblastic Leukemia in First Complete Remission

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