Monday, May 29, 2023
| Non-HCT | Allo-HCT | P | |
|---|---|---|---|
| n | 132 | 98 | |
| Age, y, median (range) | 56 (19–84) | 47 (19–71) | <.001 |
| Male sex, n (%) | 66 (50) | 58 (59) | >.05 |
| Year diagnosed, n (%) | >.05 | ||
| 2001–2009 | 39 (30) | 24 (24) | |
| 2010–2018 | 93 (70) | 74 (76) | |
| ECOG performance status, n (%) | <.001 | ||
| 0 | 23 (17) | 52 (53) | |
| 1 | 88 (67) | 45 (46) | |
| ≥2 | 21 (16) | 1 (1) | |
| KPS < 90%, n (%) | 48 (36) | 15 (15) | <.001 |
| WBC at diagnosis, n (%) | >.05 | ||
| <30 000 | 72 (55) | 47 (48) | |
| 30 000–100 000 | 33 (25) | 30 (31) | |
| >100 000 | 27 (20) | 21 (21) | |
| BM blasts, median (range) | 85 (4–98) | 81 (10–90) | >.05 |
| CNS involvement, n (%) | 9 (7) | 7 (7) | >.05 |
| BCR-ABL p190 transcript, n (%) | 110 (83) | 71 (82) | >.05 |
| Other cytogenetic changes, n (%) | 87 (67) | 36 (37) | |
| Induction regimen, n (%) | >.05 | ||
| Nonintensive induction | 11 (8) | 8 (8) | |
| Steroid + TKI only | 9 (7) | 8 (8) | |
| Intensive induction | 121 (92) | 90 (92) | |
| Hyper-CVAD-based | 113 (86) | 72 (73) | |
| AYA-inspired | 4 (3) | 12 (12) | |
| Other | 4 (3) | 6 (6) | |
| First-line TKI, n (%) | <.001 | ||
| Imatinib | 32 (24) | 39 (40) | |
| Dasatinib | 62 (47) | 53 (54) | |
| Ponatinib | 38 (29) | 6 (6) | |
| Maintenance TKI, n (%) | <.001 | ||
| Imatinib | 31 (23) | 15 (15) | |
| Dasatinib | 58 (44) | 25 (26) | |
| Ponatinib | 34 (26) | 2 (2) |
Table 1: Patient and treatment characteristics by allogeneic hematopoietic cell transplant (allo-HCT) vs non-HCT treatment
AYA, adolescent and young adult. BM, bone marrow; CNS, central nervous system; CVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone; ECOG, Eastern Cooperative Oncology Group; WBC, white blood cell count.
| Non-HCT | Allo-HCT | P | |
|---|---|---|---|
| n | 58 | 58 | |
| Age, y, median (range) | 51 (19–73) | 49.5 (19–71) | >.05 |
| Male sex, n (%) | 30 (52) | 31 (53) | >.05 |
| Year diagnosed, n (%) | >.05 | ||
| 2001–2009 | 18 (31) | 17 (29) | |
| 2010–2018 | 40 (69) | 41 (71) | |
| ECOG performance status, n (%) | >.05 | ||
| 0 | 15 (26) | 20 (34) | |
| 1 | 39 (67) | 37 (64) | |
| ≥2 | 4 (7) | 1 (2) | |
| KPS < 90%, n (%) | 13 (22) | 12 (21) | >.05 |
| WBC at diagnosis, n (%) | >.05 | ||
| <30 000 | 36 (62) | 26 (45) | |
| 30 000–100 000 | 13 (22) | 19 (33) | |
| >100 000 | 9 (16) | 13 (22) | |
| BM blasts, median (range) | 85 (4–98) | 82 (30–98) | >.05 |
| CNS involvement, n (%) | 4 (7)7 (12) | >.05 | |
| BCR-ABL p190 transcript, n (%) | 48 (83) | 39 (81) | >.05 |
| Other cytogenetic changes, n (%) | 26 (45) | 27 (47) | |
| First-line TKI, n (%) | >.05 | ||
| Imatinib | 16 (28) | 25 (43) | |
| Dasatinib | 37 (64) | 27 (47) | |
| Ponatinib | 5 (9) | 6 (10) |
Table 2: Patient characteristics in propensity matched cohorts
| Unadjusted analysis | P | ||||||
|---|---|---|---|---|---|---|---|
| Allogeneic HCT, % (n = 98) | Non-HCT, % (n = 132) | ||||||
| 1 y | 3 y | 5 y | 1 y | 3 y | 5 y | ||
| OS | 90 | 76 | 67 | 92 | 72 | 59 | .26 |
| RFS | 88 | 70 | 62 | 85 | 65 | 54 | .15 |
| CIR | 2 | 13 | 16 | 8 | 23 | 29 | .01 |
| NRM | 10 | 17 | 22 | 7 | 13 | 18 | .32 |
| GRFS | 59 | 33 | 30 | 85 | 65 | 54 | <.0001 |
| PS matched analysis | P | ||||||
| Allogeneic HCT, % (n = 58) | Non-HCT, % (n = 58) | ||||||
| 1 y | 3 y | 5 y | 1 y | 3 y | 5 y | ||
| OS | 91 | 77 | 68 | 93 | 73 | 61 | .63 |
| RFS | 88 | 67 | 63 | 84 | 64 | 52 | .42 |
| CIR | 3 | 16 | 16 | 11 | 27 | 36 | .001 |
| NRM | 9 | 17 | 21 | 5 | 9 | 11 | .06 |
| GRFS | 57 | 29 | 25 | 84 | 64 | 52 | .0001 |
Table 3: Clinical outcome by cohort
Includes 1-, 3-, and 5-y OS, RFS, CIR, NRM, and GRFS.
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
ABIM Diplomates - maximum of 1.00 ABIM MOC points
This activity is intended for hematologists, oncologists, internists, intensivists, and other physicians caring for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
The goal of this activity is for learners to be better able to describe outcomes of adult patients with Ph+ ALL treated with induction therapy, including tyrosine kinase inhibitors (TKIs), who attained complete molecular remission (CMR) within 3 months of diagnosis, comparing patients who did and did not receive allogeneic hematopoietic cell transplantation (allo-HCT) in first remission, according to a retrospective analysis of 230 patients from 5 transplant centers.
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Historically, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with poor outcomes, and allogeneic hematopoietic cell transplantation (allo-HCT) is recommended in first complete remission (CR1). However, in the tyrosine kinase inhibitor (TKI) era, rapid attainment of a complete molecular remission (CMR) is associated with excellent outcomes without allo-HCT, suggesting transplant may not be required for these patients. To test this hypothesis, we retrospectively identified adult patients with Ph+ ALL treated with induction therapy, including TKIs, and attained CMR within 90 days of diagnosis at 5 transplant centers in the United States. We compared outcomes of those who did and did not receive allo-HCT in first remission. We identified 230 patients (allo-HCT: 98; non-HCT: 132). The allo-HCT cohort was younger with better performance status. On multivariable analysis (MVA), allo-HCT was not associated with improved overall survival (adjusted hazard ratio [aHR]: 1.05; 95% CI, 0.63–1.73) or relapse-free survival (aHR: 0.86; 95% CI, 0.54–1.37) compared with non-HCT treatment. Allo-HCT was associated with a lower cumulative incidence of relapse (aHR: 0.32; 95% CI, 0.17–0.62) but higher non-relapse mortality (aHR: 2.59; 95% CI, 1.37–4.89). Propensity score matching analysis confirmed results of MVA. Comparison of reduced-intensity HCT to non-HCT showed no statistically significant difference in any of the above endpoints. In conclusion, adult patients with Ph+ ALL who achieved CMR within 90 days of starting treatment did not derive a survival benefit from allo-HCT in CR1 in this retrospective study.
The Philadelphia chromosome (Ph+) is the most common cytogenetic abnormality in adult acute lymphoblastic leukemia (ALL), occurring in ~25% of patients at diagnosis.[1] Prior to the introduction of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion protein, Ph+ ALL was associated with a poor prognosis, with an anticipatedlong-termsurvival of <20% with chemotherapy only and ~40% with consolidation allogeneic hematopoietic cell transplantation (allo-HCT).[2,3] With the integration of imatinib into the induction and consolidation phases of ALL therapy, outcomes have significantly improved.[4–8] Smaller studies employing "next-generation" TKIs (dasatinib, ponatinib, or nilotinib) have reported even better outcomes, with overall survival (OS) ranging from 46% to 86%. Multiple studies in the pre- and post-TKI era have suggested improved survival with consolidation allo-HCT in first complete remission (CR1).[3–5,9,10] However, given the rarity of adult ALL, randomized data are lacking, and the current recommendations for early allo-HCT are based on single-arm observational studies or biologic randomization studies.[9,11]
Attaining complete molecular response (CMR) after induction has long been recognized as a powerful prognostic factor in this population.[12–15] CMR rates have also improved with integration of TKIs into induction, from 38% in the pre-TKI era to 60% to 80% in the post-TKI era.[1–3,16] A case series by Short et al reported that Ph+ patients with ALL who achieve a CR with CMR, defined as BCR-ABL transcript level <0.01% by quantitative polymerase chain reaction (qPCR), had long-term survival comparable to prior cohorts undergoing allo-HCT (4-year OS rate: 66%).[17] This study, combined with previous studies, demonstrated favorable long-term outcomes with deep molecular response following induction therapy for Ph+ ALL.[12–14] However, prior analyses have been limited by small sample size and absence of comparator cohorts.
Consequently, we undertook a multicenter, retrospective study examining outcomes in adult patients with Ph+ ALL who achieve a CMR within 90 days of diagnosis and compared outcomes in those who received allo-HCT with those who did not receive allo-HCT, with the objective of clarifying the role of allo-HCT as consolidation therapy in these patients in the modern era.
