All is not lost in accelerated phase/blast crisis and after tyrosine kinase inhibitors fail in chronic myeloid leukaemia: a retrospective study of allogeneic stem cell transplant outcomes in Australia and New Zealand

Krüger, Paul-Christian; Cooney, Julian; Nivison-Smith, Ian; Dodds, Anthony J.; Bardy, Peter; Ma, Dávid; Szer, Jeff; Durrant, Simon

doi:10.1038/bmt.2016.143

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…2 Generally, patients with CML-BP are treated with a TKI combined with intensive chemotherapy followed by allogenic stem cell transplantation (SCT); survival has improved with combined modality treatment compared with that observed with use of a TKI alone. [7][8][9] To the best of our knowledge, the current study is the largest analysis of CML-BP to date, describing the clinical characteristics, prognostic factors, survival outcomes, and treatments for patients with CML-BP who received a TKI at some point during the course of CML.…”

Section: Introductionmentioning

confidence: 99%

Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients

Jain

Kantarjian

Ghorab

et al. 2017

Cancer

126

127

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Background Outcomes in blast phase CML (CML-BP) are historically dismal. We sought to analyse the characteristics, prognostic factors and survival outcomes in patients with CML-BP in the TKI era. Methods All patients with CML-BP (n=477) were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics which predicted for survival. Overall survival (OS) and failure free survival (FFS) were assessed. Optimal cut off points for specific parameters, were identified using CART (classification and regression tree). Results Median age was 53 years (range, 16 to 84); 64% were male. Eighty percent were initially diagnosed in chronic phase CML (CML-CP) median 41 months (0.7 to 298 months) before transformation to CML-BP. De-novo CML-BP occurred in 71 patients. Seventy two percent patients received TKI therapy prior to CML-BP. Initial therapy for CML-BP included, TKI alone (35%), TKI with chemotherapy (46%) and non-TKI therapies (19%). The median OS was 12 months and median FFS was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, LDH ≥1227 IU/L, platelet count <102 K/μL, no stem cell transplantation (SCT), blast phase from CP/AP and presence of chromosome 15 aberrations predicted for a significantly increased risk of death. Achievement of major hematologic response and/or complete cytogenetic response to first line treatment predicted for better survival. Combination of TKI with intensive chemotherapy followed by stem cell transplant confer the best outcome. Conclusions Patients with CML-BP continue to pose a therapeutic challenge, have dismal outcomes and require newer treatment approaches.

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Section: Introductionmentioning

confidence: 99%

Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients

Jain

Kantarjian

Ghorab

et al. 2017

Cancer

126

127

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“…Progression to either myeloid or lymphoid blast crisis 15 now occurs infrequently due to the efficacy of tyrosine kinase inhibitors 16 . Allogeneic transplantation remains an important therapy in such advanced cases, 17 which was routinely performed for CML prior to the availability of imatinib. Graft versus leukaemia effects are well established in both CML 18 and CLL, 19 and although it may be curable for patients with both conditions, toxicity limits this treatment option.…”

Section: Discussionmentioning

confidence: 99%

Combined chronic myeloid leukaemia and chronic lymphocytic leukaemia in five patients, including one with 17p deletion

Armarego

Gottlieb

Dunlop

et al. 2021

Internal Medicine Journal

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We report a series of five Australian cases of chronic lymphocytic leukaemia (CLL) occurring concurrently with chronic myeloid leukaemia (CML). Patient management including therapies and response together with clinical progress was obtained from medical records and laboratory information systems. Prior to CML diagnosis, all five had a preceding diagnosis of CLL. Three had received prior fludarabine. All received tyrosine kinase inhibitors (TKI). None required subsequent therapy for CLL. One patient had 17p deletion CLL and another patient had normal CLL cytogenetics. All currently have satisfactory blood counts with quantitative polymerase chain reaction for CML showing molecular response. All remain alive. Thus, such cases can be successfully managed by treating each haematological disorder in the usual manner. The control achieved in CML with the TKI enables satisfactory marrow function to recover in patients with concomitant CLL. The role for allograft in patients with dual malignancies is uncertain and needs to be individualised depending on control of each malignancy.

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“…Furthermore, similar responses were reported in patients with imatinib-resistant CML-BP after the treatment with the second-generation TKIs (nilotinib and dasatinib) ( 6 ). TKIs combined with intensive chemotherapy followed by allo-hematopoietic stem cell transplantation (HSCT) have improved survival of patients with CML-BP compared with that of TKI alone ( 7 , 8 ). Response to treatment is the most important prognostic factor for survival of CML-BP ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Case report: CD38-directed CAR-T cell therapy: A novel immunotherapy targeting CD38- positive blasts overcomes TKI and chemotherapy resistance of myeloid chronic myeloid leukemia in blastic phase

et al. 2022

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Resistance to tyrosine kinase inhibitor (TKI) is a tough problem in the treatment of chronic myeloid leukemia in blastic phase (CML-BP), which was often associated with acquired mutations in the kinase domain and not eliminating the leukemic stem cells. The efficacy of TKI or combination with chemotherapy in CML-BP remains unsatisfactory. Chimeric antigen receptor T (CAR-T) cell immunotherapy may overcome TKI and chemotherapy resistance. However, lack of ideal targetable antigens is a major obstacle for treating patients with myeloid malignancies. CD38 is known to be expressed on most (acute myeloid leukemia) AML cells, and its lack of expression on hematopoietic stem cells renders it as a potential therapeutic target for myeloid CML-BP. We develop a CD38-directed CAR-T cell therapy for AML, and two patients with myeloid CML-BP were enrolled (NCT04351022). Two patients, harboring E255K and T315I mutation in the ABL kinase domain, respectively, were resistant to multiple TKIs (imatinib, dasatinib, nilotinib, and ponatinib) and intensive chemotherapy. The blasts in the bone marrow of two patients exhibited high expression of CD38. After tumor reduction chemotherapy and lymphodepletion chemotherapy, 1 × 107 CAR-T-38 cells per kilogram of body weight were administered. They achieved minimal residual disease–negative and BCR::ABL1-negative complete remission and experienced grade II cytokine release syndrome manifesting as fever. Our data highlighted that CAR-T-38 cell therapy may overcome TKI and chemotherapy resistance in patients with myeloid CML-BP.

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All is not lost in accelerated phase/blast crisis and after tyrosine kinase inhibitors fail in chronic myeloid leukaemia: a retrospective study of allogeneic stem cell transplant outcomes in Australia and New Zealand

Cited by 4 publications

References 14 publications

Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients

Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients

Combined chronic myeloid leukaemia and chronic lymphocytic leukaemia in five patients, including one with 17p deletion

Case report: CD38-directed CAR-T cell therapy: A novel immunotherapy targeting CD38- positive blasts overcomes TKI and chemotherapy resistance of myeloid chronic myeloid leukemia in blastic phase

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