Final report of TKI discontinuation trial with dasatinib for the second attempt of treatment-free remission after failing the first attempt with imatinib: Treatment-free Remission Accomplished by Dasatinib (TRAD) study.

Multiple studies have reported a significant treatment-free remission (TFR) rate of 50%-60% in patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitor (TKI) therapy. However, the remaining half of these patients still require re-initiation of TKI therapy for leukaemia control. It remains unclear if TKI drugs should be switched for re-therapy in patients who failed the first TFR (TFR1) attempt. Our study attempted to determine whether dasatinib therapy after TFR1 failure post-imatinib discontinuation could improve the likelihood of TFR2. Of 59 patients who lost molecular response after imatinib discontinuation for TFR1, 55 patients (93.2%) were treated with dasatinib, of whom 49 (89.1%) regained MR4.5 or deeper response, with a median time of 1.85 months to achieve MR4.5. Dasatinib was discontinued in 35 patients for TFR2 attempt, of whom 26 patients (74.28%) lost MMR and 6 (17.14%) MR4. Risk factor analysis for the TFR2 after dasatinib discontinuation suggested three significant factors: (1) doubling time of BCR::ABL1 transcript following TFR1 attempt, (2) rapid regaining of molecular response following dasatinib therapy and (3) undetectable BCR::ABL1 transcript prior to TFR2 attempt. The present study showed that dasatinib does not increase the TFR2 rate in general, but a selected group of patients could benefit from this approach.

Changing frontline AML treatment patterns from 2013 to 2022.

The treatment patterns for patients with newly diagnosed acute myeloid leukemia (AML) were compared between 2013 and 16 and 2021-22 in a real-world setting. A significantly higher proportion of patients age 70 and over received non-intensive therapy (NIT) in 2021-22 as compared with 2013-16 (65 % vs 44 %, p = 0.014), with a corresponding reduction in the proportion receiving either intensive therapy or no antileukemic treatment. Treatment patterns among patients < age 70 were unchanged. The complete response rate in the NIT group was 69 % in 2021-22 vs. 24 % in 2013-16 (p < 0.001); the overall survival (OS) of NIT patients was 11.5 months in 2021-22 vs. 7.8 months in 2013-16. Older patients from rural areas were more likely to decline therapy than those from urban regions. The increase in the proportion of patients opting for NIT may be related to the availability of more effective treatment options. Although outcomes are improving, the OS with NIT remains suboptimal.

BCR-ABL1 transcript doubling time as a predictor for treatment-free remission failure after imatinib discontinuation in chronic myeloid leukaemia in chronic phase.

The doubling time (DT) of the BCR-ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re-growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = ln(2)/K, where x is the DT and K is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. The optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high-risk group (DT<12·75 days but >0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse-free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate-risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low-risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P < 0·001). Monthly assessment of DT helps identify high-risk patients for treatment-free remission failure with an imminent risk of molecular recurrence, and to define low-risk patients who can be spared the frequent monitoring of monthly molecular tests.

Clinical outcome of chronic myeloid leukemia patients who switch from first-line therapy with a second generation tyrosine kinase inhibitor to an alternative TKI.

While second generation tyrosine kinase inhibitors (2GTKIs) are highly effective therapies for chronic myeloid leukemia (CML), a significant minority of patients who initiate a 2GTKI will require a switch to an alternative TKI. The long-term outcomes of those who require a change in therapy after front-line 2GTKI therapy are largely undescribed. Here we describe the clinical outcomes associated with switch to an alternative TKI after first-line therapy with a 2GTKI. Of 232 patients who initiated a 2GTKI during the study period, 76 (33 %) switched to an alternative TKI. Reasons for switching included intolerance (79 %) and resistance (21 %). Among the 60 patients who switched due to intolerance, 53 (88 %) were able to achieve or maintain a major molecular response (MMR) with 5-year progression-free survival (PFS) 90.5 % (95 % CI 90.4-90.6 %). Amongst the 16 patients who switched due to resistance, 8 patients (50 %) were able to achieve MMR with 5-year PFS 80.4 % (95 % CI 80.2-80.6 %). Most patients who switched due to intolerance remained on their second-line TKI. Approximately 25 % of patients who initiate first-line 2GTKI in a real world setting will ultimately switch to an alternate TKI due to intolerance. Patients who switch for intolerance continue to enjoy excellent clinical outcomes.

Optimal duration of imatinib treatment/deep molecular response for treatment-free remission after imatinib discontinuation from a Canadian tyrosine kinase inhibitor discontinuation trial.

Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment-free remission (TFR) success after TKI discontinuation, the optimal cut-off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse-free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut-off period of time. The shortest cut-off was sought that met the joint criteria of a P value ≤ 0·05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cut-off with a P value 0·01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61·8%) compared to those with less treatment (36·0%). Also, 4·5 years MR4 duration as the shortest cut-off with a P value 0·003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4·5 years showed a higher mRFS rate (64·2%) than those with a shorter MR4 duration (41·9%).

Incremental value of the bone marrow trephine biopsy in detecting residual leukemia following treatment for Acute Myeloid Leukemia.

Most guidelines suggest that only the bone marrow aspirate (BMA) is necessary to assess residual disease following intensive chemotherapy for Acute Myeloid Leukemia (AML) with the bone marrow trephine biopsy (BMTB) recommended in cases of a poor quality BMA. We performed a retrospective study evaluating this in a cohort of patients receiving intensive chemotherapy for AML. Residual disease was assessed by morphological examination of the BMA and BMTB±immunohistochemistry. Of the 647 marrows 32.6% were interim marrows performed prior to peripheral count recovery, 41.7% were end of induction (EOI) marrows and the remaining were 'other marrows'. The BMA and BMTB findings were concordant in 92.8% of cases. The BMTB led to a change in diagnosis from 'no leukemia' to 'residual leukemia' in 5.2% of interim, 3.7% of EOI and 2.4% of 'other' marrows. The BMA alone had a sensitivity of 86.8% in detecting residual leukemia and of 82.3%, 82.5% and 94.2% for interim, EOI and 'other marrows', respectively. Despite the high concordance between the BMA and the BMTB the poor sensitivity of the BMA in detecting residual leukemia, particularly at EOI, may lead to an overestimation of the complete remission rates which may have therapeutic and clinical trial implications.

The fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) chemotherapy regimen is an alternative to anthracycline-based therapy for the treatment of acute myeloid leukemia for patients with pre-existing cardiac disease.

We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) as first-line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline-based treatment due to advanced age, significant comorbidities, or pre-existing cardiac disease. The median age was 69 (21-80); 46% received FLAG for pre-existing cardiac disease and others due to age (32%), non-cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre-existing cardiac disease. Among non-transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse-free survival was 14.7 months. The median overall survival was 9.3 months with 1- and 2-yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline-based induction for Acute myeloid leukemia in those with significant comorbidities including pre-existing cardiac disease.

Evolving Therapeutic Options for Polycythemia Vera: Perspectives of the Canadian Myeloproliferative Neoplasms Group.

Polycythemia vera (PV) is a clonal stem cell disorder characterized by erythrocytosis and associated with burdensome symptoms, reduced quality of life, risk of thrombohemorrhagic complications, and risk of transformation to myelofibrosis and acute myeloid leukemia. The discovery of the JAK2 V617 mutation marked a significant milestone in understanding the pathophysiology of the disease and subsequently the diagnostic and therapeutic approaches. The current diagnostic criteria for PV are based on hemoglobin level and presence of the JAK2 V617 mutation. The treatment is geared toward prevention of thrombotic events, normalization of blood counts, control of disease-related symptoms, and potential prolongation of survival. Cytoreductive therapy is indicated in patients at increased risk of thrombosis. Hydroxyurea (HU) remains the most commonly used first-line cytoreductive therapy and is superior to phlebotomy in reducing risk of arterial and venous thrombosis. Interferon (IFN) is used either at failure of HU or in selected patients as first-line therapy. The results of pegylated IFN in phase 2 studies appear encouraging, with molecular responses occurring in some patients. Ongoing phase 3 studies of HU versus pegylated IFN will define the optimal first-line cytoreductive therapy for PV. A recent phase 3 trial has shown the superiority of the JAK1/2 inhibitor ruxolitinib in comparison to best available treatment in HU-intolerant or -resistant patients. The therapeutic landscape of PV is likely to change in the near future. In this report, we assess the potential impact of the changing landscape of PV management on daily practice.

Quality of life following completion of treatment for adult acute lymphoblastic leukemia with a pediatric-based protocol.

Using multiple validated self-report instruments, we evaluated the health-related quality of life (HRQoL) of 29 adult ALL patients a median of 28 months after completing a pediatric-based treatment regimen. Global health was similar to normative data, but leukemia survivors had lower cognitive and social function, and reported more financial difficulty. Fatigue and pain affected 83% and 53% of patients, respectively, and both showed significant inverse correlation with overall health and all functional scales. Vincristine-related peripheral neuropathy was reported by 43%. Although therapy-related symptoms were persistent, long-term ALL survivors have a global HRQoL similar to the general population.

Outcomes of adult patients with relapsed acute lymphoblastic leukemia following frontline treatment with a pediatric regimen.

We analyzed the outcome of 46 patients with acute lymphoblastic leukemia (ALL) who relapsed following treatment with a pediatric-based protocol; 34 received intensive re-induction chemotherapy, with a CR2 rate of 62%, median overall survival (OS) 7.8 months, median relapse-free survival 5.2 months and one year OS 19%. Allogeneic HSCT was performed in 8 patients in CR2/3, with a median OS 2.2 months. OS was superior in patients who relapsed after completion of chemotherapy, compared to those relapsing on treatment. The outcome of adult ALL relapsing after treatment was therefore poor, and novel salvage strategies are needed to improve outcomes.

Familial myelodysplastic syndromes: a review of the literature.

Familial cases of myelodysplastic syndromes are rare, but are immensely valuable for the investigation of the molecular pathogenesis of myelodysplasia in general. The best-characterized familial myelodysplastic syndrome is that of familial platelet disorder with propensity to myeloid malignancy, caused by heterozygous germline RUNX1 mutations. Recently, there has been an increase in the number of reported cases, allowing for better understanding of the incidence, clinical features, and pathogenesis of this disorder. These recent cases have highlighted the clinical variability of the disorder and confirmed that many patients lack a bleeding and/or thrombocytopenia history. Additionally, several cases of T-acute lymphoblastic leukemia have now been reported, confirming a risk of lymphoid leukemia in patients with inherited RUNX1 mutations. Furthermore, an increased awareness of clinicians has helped detect a number of additional families affected by inherited myelodysplastic syndromes, resulting in the identification of novel causative mechanisms of disease, such as RUNX1 deficiency resulting from constitutional microdeletions of 21q22 and myelodysplasia-associated with telomerase deficiency. Awareness of predisposition to myelodysplastic syndromes and acute myeloid leukemia in families may be of critical importance in the management of younger patients with myelodysplasia in whom allogeneic hematopoietic stem cell transplantation is considered. Such families should be investigated for inherited deficiencies of RUNX1 and/or telomerase to prevent the use of an affected sibling as a donor for transplantation. Here we provide an update on familial platelet disorder in addition to a review of other known familial myelodysplastic syndromes.