Durable molecular response to imatinib mesylate following nonmyeloablative allogeneic stem-cell transplantation for persisting myeloid blast crisis in chronic myeloid leukemia

We report a chronic myeloid leukemia (CML) patient in chronic phase (CP) who developed blast crisis (BC) under imatinib mesylate administered in a dose reduced and non-continuous fashion because of hematologic intolerance. The patient underwent nonmyeloablative stem-cell transplant from a matched unrelated donor, but failed to achieve full donor chimerism and antileukemic response resulting in persistence of advanced disease. Complete hematologic, cytogenetic and molecular responses were attained 5 weeks after readministration of regularly dosed imatinib and two-step nested RT-PCR confirmed molecular remission throughout a 6 month follow-up period. This is the first case demonstrating that imatinib mesylate is a highly effective and safe treatment option to induce durable molecular remission in patients with CML who remain in myeloid blast crisis after nonmyeloablative allogeneic stem-cell transplantation.     

The graft-versus-leukemia effect of nonmyeloablative stem cell allografts may not be sufficient to cure chronic myelogenous leukemia

We treated 12 patients with chronic myelogenous leukemia (CML) with a low-intensity preparative regimen followed by allogeneic stem cell transplantation in an attempt to confer a curative graft-versus-leukemia (GVL) effect with minimum morbidity. Seven patients in first chronic phase (CP1) and five in second chronic phase (CP2) (age 15-68 years) received a nonmyeloablative conditioning regimen of fludarabine and cyclophosphamide, followed by a G-CSF-mobilized peripheral blood stem cell (PBSC) transplant from an HLA-identical sibling. Cyclosporine (CsA) was used for graft-versus-host disease (GVHD) prophylaxis. Median follow-up was 384 days. Neutrophil recovery occurred at a median of 12 days. There was no transplant-related mortality. Of the seven CP1 patients transplanted, seven achieved a stable molecular remission; two with no post-transplant intervention, three after donor lymphocytes, imatinib and interferon, and two after a myeloablative stem cell transplant. Four of five CP2 patients died in blast crisis and one survived in molecular remission. Of the 12 patients with durable engraftment, six had Grades II-IV acute GVHD; six had limited chronic GVHD. These results suggest that cytoreduction is required to optimize the curative effect of allogeneic stem cell transplantation for CML.     

Early allogeneic stem cell transplantation for chronic myelogenous leukemia in the imatinib era: a preliminary assessment

We have examined the role of early allogeneic hematopoietic stem cell transplantation in patients with chronic phase chronic myelogenous leukemia (CML) who enter a complete cytogenetic remission with imatinib mesylate. Three kinds of data were used to examine the effect of the outcome of current BCR-ABL inhibitor treatment compared to early allogeneic stem cell transplantation: (1) the life expectancy of the general population of the United States as a function of age, (2) the life expectancy of CML patients as a function of the age of patients treated with imatinib mesylate (imatinib) who achieve a complete cytogenetic remission, and (3) the life expectancy of patients with CML treated with matched-related or matched-unrelated stem cell transplantation as a function of age, derived from data provided by the Center for International Blood and Marrow Transplant Research (CIBMTR). We also considered separately the transplant results of the Fred Hutchinson Cancer Research Center (FHCRC), which are substantially better than the "average" outcome from the CIBMTR. We have calculated the projected life expectancy from the age at which patients with CML enter complete cytogenetic remission with imatinib and that of those who receive allogeneic stem cell transplantation. The outcome with imatinib therapy of newly diagnosed patients with CML has been documented for only 4 and 1/2 years, whereas transplant data were available for up to 25 years. Thus, in order to compare life expectancy and 10-year survival probability, it was necessary to extrapolate the imatinib data. A basis for extrapolation is offered and conservative estimates have been used for comparison. Our best estimate is that patients receiving imatinib who have a complete cytogenetic remission have a higher projected probability of 10-year survival than patients who are transplanted, based on results provided by the CIBMTR, and have about the same probability compared to the data from the Fred Hutchinson Cancer Center for patients in the 30- to 60-year-old range. The mathematical approach used here permits reexamining the analysis using future data on BCR-ABL inhibitor therapy or allogeneic stem cell transplantation therapy or both.     

Imatinib mesylate-sensitive blast crisis immediately after discontinuation of imatinib mesylate therapy in chronic myelogenous leukemia: report of two cases

Although imatinib mesylate has shown encouraging activity in chronic myelogenous leukemia (CML), disease progression during therapy has been observed, manifested by clonal expansion of imatinib mesylate-resistant leukemia cells. On the other hand, myelosuppression related to treatment of imatinib mesylate is often managed with temporary interruption of treatment or dose reduction. We here report two CML patients who had imatinib mesylate-sensitive blast crisis (BC) immediately after discontinuation of imatinib mesylate therapy. The patients discontinued therapy because of neutropenia. Although there was no evidence of blastic phase during therapy, BC occurred 2 weeks after the withdrawal of treatment in both cases. Interestingly, additional chromosomal abnormalities were detected following the withdrawal of imatinib mesylate and disappeared by re-introduction of this agent. The same doses of imatinib mesylate was still effective and remission was sustained with imatinib mesylate alone again. Our report suggests the possibility that withdrawal of imatinib mesylate may lead to proliferation of blast clones even in patients showing good responses to imatinib mesylate without signs of disease progression.     

Stable molecular remission induced by imatinib mesylate (STI571) in a patient with CML lymphoid blast crisis relapsing after allogeneic stem cell transplantation

We report the response to the ABL kinase inhibitor imatinib mesylate (STI571) in a patient with chronic myeloid leukemia (CML) who relapsed twice after dose-reduced allogeneic stem cell transplantation (alloSCT) for B lymphoid blast crisis (BC) and failed to develop an antileukemic response despite grade 3 graft-versus-host disease (GvHD). Complete hematologic, cytogenetic and molecular responses were achieved within 9 weeks of therapy and are maintained after 27 months. Extensive chronic skin GvHD necessitating immunosuppressive therapy developed after 14 months. This case illustrates the ability of imatinib to induce sustained hematologic and molecular remissions in some patients relapsing with advanced stage CML after alloSCT.     

Allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in second chronic phase attained by imatinib after onset of blast crisis

The prognosis for patients with chronic myeloid leukemia (CML) in blast crisis (BC) remains dismal even with the availability of the BCR-ABL tyrosine kinase inhibitor imatinib, since it only offers short-term benefit in most cases. Allogeneic hematopoietic stem cell transplantation (HSCT) seems to be a viable option for BC-CML patients who attained remission. We treated ten patients with ablative allogeneic HSCT, who achieved second chronic phase (CP) by the use of imatinib after onset of BC. Median patient age was 32 years (range 17–46). Among them, four patients received HSCT from human leukocyte antigen mismatched haplo-identical family donors. After a median follow-up of 24 months (range 8–42), six out of the ten patients were alive in durable complete cytogenetic remission, one patient died in relapse 4 months after transplantation, the others died of severe acute graft-versus-host disease and associated infections. No unusual organ toxicities and engraftment difficulties were observed. Extensive chronic GVHD developed in three of six patients who could be evaluated. Patients transplanted with haplo-identical donors had a high treatment-related modality. Allogeneic HSCT may represent a feasible treatment for patients with CML in second CP attained by imatinib after onset of BC especially when a suitable donor is available.     

Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia

A survival benefit for imatinib mesylate versus interferon-alpha therapy could not be demonstrated in the randomized study in newly diagnosed Philadelphia chromosome (Ph)-positive chronic-phase chronic myelogenous leukemia (CML) due to the high rate of crossover (90%) from interferon-alpha to imatinib mesylate within a year of study entry. We compared survival in 279 patients with newly diagnosed CML treated with imatinib mesylate at our institution (2000-2004) to 650 patients treated with interferon-alpha (1982-1997). The complete cytogenetic response rates were 87% with imatinib mesylate and 28% with interferon-alpha (P < .001). The estimated 3-year survival rates were 96% with imatinib mesylate and 81% with interferon-alpha (P < .01). Survival rates with imatinib mesylate were significantly better than with interferon-alpha within each of the CML prognostic risks groups. By multivariate analysis, imatinib mesylate therapy was identified as an independent favorable prognostic factor, after accounting for the impact of pretreatment factors (hazard ratio, 0.44; P < .01). By landmark analysis at 12 months, survival within each cytogenetic response category was similar with imatinib mesylate or interferon-alpha, suggesting that the survival benefit of imatinib mesylate (versus interferon-alpha in newly diagnosed CML) is through improving cytogenetic response.     

A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem cell transplantation

Imatinib mesylate is highly effective in relapsed chronic myelogenous leukemia (CML) after allogeneic hematopoetic stem cell transplantation (HSCT). However, it is unknown whether imatinib produces durable molecular remissions. The outcome of CML patients transplanted at our center who had received only imatinib for relapse after HSCT was compared with that of patients treated with donor lymphocyte infusions (DLI). Imatinib therapy resulted in a higher incidence of relapse and inferior leukemia-free survival (p=0.006 and p=0.016, respectively). These data suggest that imatinib alone probably does not cure relapse after HSCT.     

Clinical and genetic studies of ETV6/ABL1-positive chronic myeloid leukaemia in blast crisis treated with imatinib mesylate

Most chronic myeloid leukaemia (CML) patients are genetically characterized by the t(9;22)(q34;q11), generating the BCR/ABL1 fusion gene. However, a few CML patients with rearrangements of 9q34 and 12p13, leading to ETV6/ABL1 chimaeras, have also been reported. Here we describe the clinical and genetic response to imatinib mesylate treatment of an ETV6/ABL1-positive CML patient diagnosed in blast crisis (BC). A chronic phase was achieved after acute myeloid leukaemia induction therapy. Then, treatment with imatinib mesylate (600 mg/d) was initiated and the effect was assessed clinically as well as genetically, including by repeated interphase fluorescence in situ hybridization studies. Until d 71 of imatinib mesylate therapy, stable improvements in the clinical and laboratory features were noted, and the frequency of ABL1-rearranged peripheral blood cells decreased from 56% to 11%. At d 92, an additional t(12;13)(p12;q13), with the 12p breakpoint proximal to ETV6, was found. The patient relapsed into BC 126 d after the start of the imatinib mesylate treatment and succumbed to the disease shortly afterwards. No mutations in the tyrosine kinase domain of ABL1 of the ETV6/ABL1 fusion were identified in the second BC. However, whereas the ETV6/ABL1 expression was seemingly the same at diagnosis and at second BC, the expression of ETV6 was markedly lower at the second BC. This decreased expression of wild-type ETV6 may have been a contributory factor for the relapse.     

Treatment options for newly diagnosed patients with chronic myeloid leukemia

Chronic myeloid leukemia (CML) is characterized by a 9:22 translocation resulting in production of a chimeric BCR-ABL fusion protein that has constitutive tyrosine kinase activity and drives leukemic transformation. Imatinib mesylate, a selective inhibitor of BCR-ABL, has been introduced into clinical trials with favorable toxicity and impressive activity at all disease stages. In a phase III study of diagnosed chronic phase CML, imatinib mesylate was superior to interferon plus cytarabine in cytogenetic response, freedom from disease progression, and tolerability. Hematopoietic stem cell transplantation remains the only established cure for CML. Recent reports show continued improvements with survivals after matched sibling grafts greater than 80% at 3 to 5 years. Therefore, recent advances in conventional and transplant therapy have improved treatment options for newly diagnosed patients. Sensitive and specific monitoring techniques developed for CML may help further refine treatment with regard to using these and other emerging therapies.     

Molecular remission of CML after autotransplantation followed by adoptive transfer of costimulated autologous T cells

Four patients with chronic myelogenous leukemia (CML) that was refractory to interferon alpha (two patients) or imatinib mesylate (two patients), and who lacked donors for allogeneic stem cell transplantation, received autotransplants followed by infusions of ex vivo costimulated autologous T cells. At day +30 (about 14 days after T-cell infusion), the mean CD4+ cell count was 481 cells/microl (range 270-834) and the mean CD8+ count was 516 cells/microl (range 173-1261). One patient had a relative lymphocytosis at 3.5 months after T-cell infusion, with CD4 and CD8 levels of 750 and 1985 cells/microl, respectively. All the four patients had complete cytogenetic remissions early after transplantation, three of whom also became PCR negative for the bcr/abl fusion mRNA. One patient, who had experienced progressive CML while on interferon alpha therapy, became PCR- post transplant, and remained in a molecular CR at 3.0 years of follow-up. All the four patients survived at 6, 9, 40, and 44 months post transplant; the patient who remained PCR+ had a cytogenetic and hematologic relapse of CML, but entered a molecular remission on imatinib. Autotransplantation followed by costimulated autologous T cells is feasible for patients with chronic phase CML, who lack allogeneic donors and can be associated with molecular remissions.     

Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment

Imatinib mesylate treatment markedly reduces the burden of leukemia cells in chronic myelogenous leukemia (CML) patients. However, patients remain at risk for relapse on discontinuing treatment. We have previously shown that residual BCR-ABL(+) progenitors can be detected in CML patients within the first 2 years of imatinib treatment. However, reduced rates of relapse and continued decline of BCR-ABL levels with prolonged treatment, together with the ability of selected patients to maintain remission after discontinuing treatment, led us to investigate whether prolonged imatinib exposure resulted in reduction or elimination of BCR-ABL(+) stem cells. We evaluated BCR-ABL expression in CD34(+)CD38(+) (38(+)) committed progenitors and CD34(+)CD38(-) (38(-)) stem/primitive progenitor cells in samples from CML patients on imatinib treatment for at least 4 years with cytogenetic and molecular response. High levels of BCR-ABL expression were maintained over time in the 38(-) stem cell fraction. The absolute frequency of BCR-ABL(+) cells as determined by limiting dilution analysis was consistently higher in 38(-) compared with 38(+) cells. Transplantation into NOD/SCID-IL2Rγ-chain knockout mice demonstrated that BCR-ABL(+) cells had long-term in vivo repopulating capacity. These results directly demonstrate that BCR-ABL(+) stem cells persist in CML patients despite prolonged treatment with imatinib, and support ongoing efforts to target this population.     

Excellent outcomes of children with CML treated with imatinib mesylate compared to that in pre-imatinib era

Allogeneic hematopoietic stem cell transplantation (HSCT) and tyrosine kinase inhibitor have revolutionized the treatment of patients with chronic myeloid leukemia (CML). In this study, the clinical impact of HSCT and imatinib mesylate (IM) was retrospectively analyzed in 28 children with CML treated in our institutes from 1984 to 2008. Twelve patients were given oral IM. At 36?months after initiation of IM therapy, the complete cytogenetic response rate was 90.9%, and the major molecular response rate was 36.4%. Sixteen children received allogeneic HSCT without administration of IM. The stage of disease at transplantation was: first chronic phase (n?=?10), second chronic phase (n?=?2), accelerated phase (n?=?2), and blastic crisis (n?=?2). The progression rate was significantly lower in patients treated with IM than in those treated without IM (0 vs. 28.6%, p?=?0.006). In summary, the survival outcomes of pediatric patients with CML were dramatically improved by treatment with IM compared to HSCT.     

Effect of LMO2 protein expression on survival in chronic myeloid leukemia patients treated with imatinib mesylate

Abstract

LIM domain only-2 (LMO2) is an important regulator of hematopoietic stem cell development. LMO2 protein is expressed in all three hematopoietic lineages precursors of the hematopoietic system, and its expression has been shown to decrease gradually during differentiation. Chronic myeloid leukemia (CML) is a malignant clonal myeloproliferative disorder in which the terminal differentiation is not altered until the appearance of an accelerated or blast phase. We examined whether LMO2 protein expression can predict outcome CML patients undergoing tyrosine kinase inhibitor therapy, imatinib mesylate (IM). Immunohistochemistry on bone marrow biopsy material for LMO2 protein was performed in 47 CML patients. We report that the LMO2 protein expression is correlated with improved hematologic remission and overall survival in the CML patients treated with IM. The immunohistologic analysis of LMO2 protein expression may become a predictive factor for anticipating the treatment responses of CML patients.     

Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure

Resistance to imatinib mesylate is an emerging problem in the treatment of chronic myeloid leukemia (CML), often associated with point mutations in the Bcr-Abl kinase domain. Outcome of patients with such mutations after allogeneic stem cell transplantation (Allo-SCT) is unknown. Ten imatinib-resistant patients with Bcr-Abl kinase mutations received a transplant: 9 had CML (3 in chronic phase, 4 in accelerated phase, and 2 in blast phase) and 1 had Philadelphia-positive acute lymphocytic leukemia (ALL). Patients harbored 9 different protein kinase mutations (T315I mutation, n = 2). Preparative regimens were ablative (n = 7) and nonablative (n = 3). All patients engrafted; there were no treatment-related deaths. Disease response was complete molecular (CMR; n = 7), major molecular (n = 2), and no response (n = 1). Three patients (mutations Q252H, E255K, and T315I) died of relapse after Allo-SCT. Seven patients are alive (6 in CMR) for a median of 19 months. Allo-SCT remains an important salvage option for patients who develop resistance to imatinib through Bcr-Abl mutations.     

Imatinib mesylate therapy may overcome the poor prognostic significance of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia

Deletions of derivative chromosome 9 [der(9)] can be identified by fluorescence in situ hybridization (FISH) in 10% to 15% of patients with chronic myeloid leukemia (CML). Patients with der(9) deletions have been reported to have an adverse outcome when treated with chemotherapy, interferon, and possibly imatinib mesylate. We investigated the frequency and prognostic significance of der(9) deletions among 352 patients with CML treated with imatinib mesylate at our institution, in whom a deletion status of der(9) was determined. Thirty-three patients (9%; 95% CI 0.07, 0.13) (30 in chronic phase, 3 in accelerated phase) had der(9) deletions. The rates of major (82% vs 79%, P = 0.82) and complete cytogenetic response (76% vs 66%, P = .33) with imatinib mesylate therapy were similar in patients with and without der(9) deletions, respectively. After a median follow-up of 28 months, there was no difference in overall survival (P = .30) or response duration (P = .49) in patients with and without deletions. In a multivariate analysis, der(9) deletions had no significant impact on response, survival, or response duration. We conclude that treatment with imatinib mesylate overcomes the adverse prognostic significance of der(9) deletions in patients with CML.     

Management of chronic myeloid leukaemia in relapse following donor lymphocyte infusion induced remission: a retrospective study of the Clinical Trials Committee of the British Society of Blood & Marrow Transplantation (BSBMT)

Donor lymphocyte infusion (DLI) can restore remission in a high percentage of patients with chronic myeloid leukaemia (CML) who relapse after allogeneic stem cell transplant (SCT). Subsequent relapses after a DLI-induced remission do occur and the optimal management of these patients is not defined. A retrospective study of the practice of UK transplant centres was conducted. In all, 13 patients from seven centres were identified: all were treated for relapse post allogeneic SCT with DLI and achieved either a complete cytogenetic (n=5) or molecular (n=8) remission. All patients subsequently had a second relapse, at molecular (n=7), cytogenetic (n=4) and haematological (n=2) levels. Further DLI was used in the treatment of 11 patients, imatinib mesylate in three and chemotherapy in two. The two patients with haematological relapse died of blastic disease. The remaining 11 patients achieved either a complete cytogenetic (n=2) or molecular (n=9) remission. Nine patients remain in molecular remission at a median follow-up of 29 months, seven of whom had received DLI alone as treatment for second relapse, one DLI plus imatinib and one imatinib alone. Toxicity following DLI for second relapse was low. Longer follow-up will be required to see if these second DLI-induced remissions will be durable.     

Optimal initial therapy for patients with newly diagnosed chronic myeloid leukemia in chronic phase

PURPOSE OF REVIEW: Imatinib mesylate, a tyrosine kinase inhibitor, has revolutionized the therapy of newly diagnosed patients with chronic myeloid leukemia. Prior to imatinib, treatment algorithms for chronic myeloid leukemia patients recommended stem cell transplantation for patients less than 50 years old who had a donor and could undergo stem cell transplantation. Other than stem cell transplantation, interferon was the only drug that could induce cytogenetic remissions in minority of patients. RECENT FINDINGS: After 5 years of follow-up, the rate of relapse with imatinib therapy continues to decrease, and the numbers of patients achieving a complete molecular response continue to increase. In addition, with a longer follow up, imatinib continues to be safe and easily tolerated. Recent studies have shown a survival benefit with imatinib. The use of imatinib before stem cell transplant did not have an effect on mortality or morbidity posttransplant. SUMMARY: Currently, imatinib is considered first line therapy in all patients with early chronic phase chronic myeloid leukemia with stem cell transplant reserved for patients who have disease resistant to imatinib therapy. Our aim is to review current recommendations for initial therapy of patients with early chronic phasechronic myeloid leukemia, current areas of controversy and future directions.