Tyrosine Kinase Inhibitor Sequencing in Patients with Chronic Myeloid Leukemia

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The significance of early warning in chronic myeloid leukemia

We have read with great interest the manuscript by Eskazan and colleagues entitled \u201cCritical appraisal of European LeukemiaNet (ELN) 2013 recommendations for the management of chronic myeloid leukemia: is it early for a warning?\u201d. After a revision of the relatively limited literature, the Authors conclude that there are still no solid data to suggest a switch of therapy in patients with warning signs and that long-term survival remains a highly significant endpoint in CML patients. While we generally agree with these thoughts, we would like to stress a couple of additional points on the issue of ELN 2013 \u2013 defined \u201cwarning\u201d. The ELN recommendations defines warning as less than partial cytogenetic response (PCyR) and/or BCR-ABL1 >10% (according to the International Scale \u2013 IS) at 3 months, less than complete cytogenetic response (CCyR) and/or BCR-ABL1 >1%IS at 6 months, and BCR-ABL1 >0.1% IS, i.e. no major molecular response (MMR) at 12 months. So, at the first two time-points, conventionally considered as \u201cearly\u201d, both cytogenetic and molecular status define response, while at 12 months only BCR-ABL1 level >0.1 to 1%IS identifies warning patients, as anything less than CCyR is regarded as a failure. Our group analyzed the outcome of 216 CML patients treated with front-line standard dose (400 mg/day) imatinib with discordant cytogenetic and molecular responses at 3 and 6 months. Patients with even a single warning sign at 3 months (i.e. no PCyR or BCR-ABL1 >10%IS) had a significantly lower chance to obtain a subsequent CCyR (37% compared to 85% in patients with concordant optimal cytogenetic and molecular responses) and worse failure-free survival (FFS) (39% vs 81% at 48 months). Similarly, a warning sign at 6 months identified patients less prone to attain a MMR at 12 months (17% vs 82% in concordantly optimal patients) and with worse FFS (62% vs 88%). In our experience, most discordant patients had a \u201cmolecular warning\u201d, as 15/17 discordant at 3 months were in PCyR or better but with BCR-ABL1 transcript >10%IS and at 6 months 20/25 discordant were in CCyR with BCR-ABL1 >1%IS. This finding is an indirect confirmation of the importance of a BCR-ABL1 transcript level <10%IS at 3 months (now defined \u201cearly molecular response\u201d, EMR) as a positive predictor of long-term outcome, as reported by different studies. Despite EMR is gaining ground as a factor for an early switch of therapy, as suggested by NCCN guidelines, some reports indicate, in line with ELN recommendations, to consider also the 6-month cytogenetic or molecular status to assess a two-point evaluation of response to TKI therapy. The MDACC group analyzed the outcome of 453 CML patients treated with different TKIs, finding that 19 out of 44 patients (43%) not achieving major (i.e. optimal) cytogenetic response (MCyR) at 3 months obtained this response at 6 months and had an outcome comparable to patients achieving an earlier MCyR [8]. A Canadian study reviewed 320 patients receiving imatinib therapy with 3 and 6 month BCR-ABL1 transcript levels available, reporting that patients not achieving an EMR at 3 months but with BCR-ABL1 transcript <1% at 6 months (n=18) had similar FFS, progression-free survival (PFS) and overall survival (OS) compared to patients in EMR (n=184). Taken together, these data suggest that cytogenetic and molecular response at 6 months can identify a subgroup with favorable outcome among patients \u201cwarning\u201d at 3 months. However, considering patients with cytogenetic and/or molecular warning at 3 months in our series (n=41), only 2 had a subsequent optimal cytogenetic and molecular response at 6 months (unpublished). Moreover, we found that the rates of warning responses at 3 and 6 months were higher in cases with b2a2 BCR-ABL1 transcript type compared to those with b3a2 variant (32% vs 24% at 3 months and 31% vs 12% at 6 months, respectively). If there is still debate on the practical significance of a warning at 3 or 6 months, even less consensus and significantly less data are about the meaning of a late (i.e. at 12 months) warning. Starting from their database of 483 patients treated with four different TKI strategies, colleagues at MDACC found no benefit, in term of survival, in patients achieving MMR while in CCyR, even if their landmark analysis was performed at 18 and 24 months, and not at the 12-months timepoint. A landmark analysis of PFS and OS on the bases of molecular response at 12 months of imatinib performed in 128 patients from our database did not find any difference between patients in MMR or not (personal data, unpublished). Concordantly, a Spanish group showed that, in 198 patients treated with standard-dose imatinib and in CCyR without MMR at 12 months, a switch to a second-generation TKI was associated with a higher probability of subsequently major and deep molecular response, but no advantage in terms of PFS and OS and higher rates of discontinuation for adverse events, compared to patients continuing imatinib. Hopefully, more information on the therapeutic approach to \u201cwarning\u201d patients will come from an upcoming study of the GIMEMA Working Party on CML study aimed to evaluate efficacy of nilotinib frontline versus imatinib followed by switch to nilotinib in the case of absence of ELN-defined optimal response at 3, 6 or 12 months

How could patient reported outcomes improve patient management in chronic myeloid leukemia?

Introduction: Patients reported outcome (PRO) are still under-used in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs), though data on the correlation between quality of life (QoL) and therapeutic efficacy are increasingly known. Chronic low-grade toxicities can reduce patient's QoL and negatively impact on adherence.Areas covered: This review will focus on the role of QoL questionnaires in patients with CML, receiving imatinib or newer TKIs (dasatinib, nilotinib, bosutinib, ponatinib). Physicians tend to underestimate the impact of TKI-related symptoms, in particular fatigue, that negatively affect QoL and can be a reason of poor adherence to therapy, with detrimental effect on long-term response. Few studies pointed out the role of PRO in CML, and there is paucity of questionnaires specifically designed for CML patients.Expert commentary: We recommend a wider use of PRO to join the pursuit of a rapid and deep responses with an optimization of QoL

Splenectomy in Myelofibrosis: Indications, Efficacy, and Complications

Splenomegaly, which may range from a few centimeters below the left costal border to massive dimensions, is one of the most characteristic features in patients with advanced myelofibrosis (MF). Splenectomy may offer an effective therapeutic option for treating massive splenomegaly in patients with MF, and especially in cases of disease refractory to conventional drugs, but it is associated with a number of complications as well as substantial morbidity and mortality. Whether splenectomy should be performed before allogeneic hematopoietic stem-cell transplantation is also controversial, and there is a lack of prospective randomized clinical trials that assess the role of splenectomy before hematopoietic stem-cell transplantation in patients with MF. Although splenectomy is not routinely performed before transplantation, it may be appropriate in patients with massive splenomegaly and related symptoms, so long as the higher risk of graft failure in such cases is taken into account. This review aims to describe the efficacy, indications, and complications of splenectomy in patients with MF; and to evaluate the long-term impact of splenectomy on patient survival and risk of disease transformation

Cryptic BCR-ABL fusion gene as variant rearrangement in chronic myeloid leukemia: Molecular cytogenetic characterization and influence on TKIs therapy

At diagnosis, about 5% of Chronic Myeloid Leukemia (CML) patients lacks Philadelphia chromosome (Ph), despite the presence of the BCR/ABL rearrangement. Two mechanisms have been proposed about the occurrence of this rearrangement: the first one is a cryptic insertion between chromosomes 9 and 22; the second one involves two sequential translocations: a classic t(9;22) followed by a reverse translocation, which reconstitutes the normal morphology of the partner chromosomes. Out of 398 newly diagnosed CML patients, we selected 12 Ph-negative cases. Six Ph-negative patients treated with tyrosine kinase inhibitors (TKIs) were characterized, in order to study the mechanisms leading to the rearrangement and the eventual correlation with prognosis in treatment with TKIs. FISH analysis revealed cryptic insertion in 5 patients and classic translocation in the last one. In more detail, we observed 4 different patterns of rearrangement, suggesting high genetic heterogeneity of these patients. In our cases, the BCR/ABL rearrangement mapped more frequently on 9q34 region than on 22q11 region, in contrast to previous reports. Four patients, with low Sokal risk, achieved Complete Cytogenetic Response and/or Major Molecular Response after TKIs therapy. Therapy resistance was observed in one patient with duplication of BCR/ABL rearrangement and in another one with high risk. Even if the number patient is inevitably low, we can confirm that the rare Ph-negative CML patients do not constitute a "warning" category, meanwhile the presence of further cytogenetic abnormalities remains an adverse prognostic factor even in TKI era