Complete Hematologic Response Rate Research Articles

Long-Term Efficacy of Dasatinib in Chronic-Phase CML: Results from the Phase I Trial (CA180002).

Imatinib resistance in CML is frequently associated with BCR-ABL mutations. Such kinase domain mutations are emerging as a common mechanistic theme in cases of acquired resistance to kinase inhibitor therapy. Five-year follow-up from the IRIS trial indicates that the incidence of hematologic resistance to imatinib is 17% and >30% of patients have discontinued imatinib therapy on study. Preclinical studies reveal that dasatinib (SPRYCEL®), a novel BCR-ABL inhibitor, is 325-fold more potent than imatinib in inhibiting the kinase activity of BCR-ABL, as well as demonstrating activity against all imatinib-resistant BCR-ABL mutations tested to date, with the exception of T315I. Here we present an update of a Phase-I dose-escalation study, with enrollment between November 2003 and April 2005, of dasatinib in imatinib-resistant or -intolerant patients with CML or Ph+ ALL; this report focuses on the long-term follow-up of the 45 patients (56% male) with late chronic-phase disease. Dasatinib was administered at doses of 15–180 mg/day on a QD or BID schedule. Median duration of CML prior to entry was 8 years (range 1–17). Median age was 63 years (range 28–79). Prior therapy included interferon-α in 91% of patients and stem-cell transplantation in 4%; 62% had received prior imatinib doses >600 mg. With a minimum follow-up of 27 months, the rate of complete hematologic response (CHR) was 91% (41/45). Major cytogenetic responses (MCyR) were attained in 51% of patients (23/45), with complete CyR (CCyR) in 44% (20/45). The rates of CCyR for the QD and BID schedules were 45% (10/22) and 43% (10/23), respectively. The median duration of CHR and MCyR have not been reached with a median duration of treatment of 28 months. In a landmark analysis, the 36-month progression-free survival (PFS) rate was 87% and overall survival (OS) was 94% for patients who achieved a MCyR within the first year of dasatinib therapy. For patients who did not achieve a MCyR within the first year, the 36-month PFS figure was 28% and OS was 68%. These long-term data confirm the durability and depth of hematologic and cytogenetic response associated with dasatinib in patients who have failed treatment with imatinib. Evidence is also provided to substantiate that the significant response rates observed with dasatinib therapy in this population translate into prolonged progression-free and overall survival. Dasatinib therefore has the potential to positively impact on the natural history of CML.

Prognostic Impact of Deletions of Derivative Chromosome 9 on Patients (pts) with Chronic Myelogenous Leukemia (CML) in Chronic Phase Treated with Nilotinib or Dasatinib.

Background: Submicroscopic deletions of the derivative chromosome 9 [del der(9)] mapping to regions adjacent to the translocation breakpoints occur in 9% to 15% of patients with CML. Deletion of der(9) is powerful prognostic indicator associated with an unfavorable prognosis in patients treated with interferon-alpha (IFN-α)-based therapies. Imatinib is currently the standard treatment for patients with CML and it appears to overcome the adverse prognostic impact imparted by deletions of der(9).Methods: We tested the prognostic impact of the deletions of der(9) in 323 patients with CML treated at our institution with the 2nd generation tyrosine kinase inhibitors (TKIs) nilotinib (n=144) or dasatinib (n=179). The presence of deletions of der(9) was investigated by FISH analysis using the LSI-BCR/ABL-(ES) probe (Vysis, Downers Grove, IL) in 244 patients. The median age was 55 years (range, 15–83) and the median follow-up was 18 months (range, 1–44). The primary endpoints evaluated were survival, complete hematologic response (CHR) and cytogenetic responses.Results: Twenty-eight (12%) patients were found to have del der(9) and 216 an intact der(9). Among patients with deletions, 16 were in chronic phase (CP), 8 in accelerated phase (AP), and 4 in blast phase (BP) at the start of nilotinib or dasatinib therapy. In the group of patients without deletions, 112 were in CP, 54 in AP and 50 in blastic phase (BP). Overall, 222 (91%) of 244 patients were assessable for response. There was no significant difference between patients with or without deletions regarding the rate of CHR, major (MCyR) or complete (CCyR) cytogenetic responses, and event-free (EFS), and overall (OS) survival at 12 months for the total population.CML Phasedeletion der(9) [No. Patients]CCyR (%)pEFS (12 months)pOS (12 months)pNo (112)721840.2970.01ChronicYes (16)737892Not Done (30)No (54)310.7540.22690.62AcceleratedYes (8)387588Not Done (27)No (50)24190.56300.56BlasticYes (4)252525Not Done (22)Among pts in CP there was no difference in response rate or EFS, but pts without del der(9) had an improved OS at 12 months compared with those carrying der(9) (97% vs 92%; p=0.01). There appears to be no significant difference between pts treated with nilotinib and those treated with dasatinib.Conclusion: Our results suggest that although the outcome of patients with CML treated in AP or BP with either nilotinib or dasatinib does not differ regardless of their deletion status, those in CP carrying del der(9) deletions may have a worse overall survival than their counterparts without deletions. This is in contrast to what has been reported with imatinib therapy. The reason for this difference is unclear.

Prognostic Significance of Prior Best Response to Imatinib in Patients (pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Treated with Second Generation Tyrosine Kinase Inhibitors (TKIs).

Backgound. Imatinib mesylate therapy has significantly improved the prognosis of CML. A minority of pts in CP-CML are primary resistant to imatinib or develop resistance during treatment. Second generation TKIs such as dasatinib and nilotinib demonstrated efficacy in overcoming imatinib resistance, with high rates of hematologic and cytogenetic responses in CML post imatinib failure.Study Aims and Study Group. We assessed the impact of prior best response to imatinib on outcome of 120 pts in CP treated with new TKIs at our institution after imatinib failure: 75 (62%) received dasatinib and 45 (38%) recived nilotinib. Median age was 57 years (range, 21–83). The median duration of the disease was 67 months (range, 4–241). Pts have been followed for a median of 22 months (range, 1–44) from the start of 2nd generation TKIs.Results. Best response to imatinib was hematologic in 47 pts (40%) and cytogenetic in 60 (50%) (complete in 28, partial in 16, minor in 16). Five pts (4%) were primary refractory and 8 (6%) were intolerant. At the start of 2nd generation TKIs, 87 pts (73%) were in active CP with no complete hematologic response (CHR). Eighty-five (71%) harbored more than 90% Philadelphia-positive metaphases, and clonal evolution was noted in 28 pts (23%). Patients that had achieved a cytogenetic response at any time during their imatinib therapy had a better outcome than those who had only a hematologic response: CHR rates 98% vs 68%, p <0.001; major cytogenetic response (MCyR) rates 75% vs 26%, p<0.001; and complete cytogenetic response (CCyR) rates 68% vs 23%, p<0.001. This translated into an improved 12-month event-free survival (EFS) of 92% vs 68% (p<0.001) and a trend for better 12-month survival of 92% vs 89% (p=0.06) (Table1). Pts with CHR at the start of therapy with 2nd generation TKIs had higher rates of cytogenetic response than those not already in CHR (88% vs 64%; p=0.01). Low disease burden defined by Philadelphia-positive metaphases <90% was associated with higher rates of hematologic response (p=0.006), MCyR (p<0.001) and CCyR (p=0.003), with no impact on EFS. There was no difference in activity between the two 2nd generation TKIs with CHR rates of 89% and 80% (p=0.18), MCyR rates of 57% and 51% (p=0.57) and CCyR rates of 52% and 47% (p=0.71) for dasatinib and nilotinib, respectively.Conclusion. The probability of response to 2nd generation TKIs is highly dependent on prior response to imatinib and disease burden at the start of therapy.Table 1% CG response% 12-MonthBest response to imatinibN% CHRMajorCompleteEFSSurvivalNo CHR48040408080CHR326826236889Any CG response599875689292P-value<0.001<0.001<0.001<0.0010.06EFS=Event-free survival; CG=Cytogenetic; CHR=complete hematologic response

IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib.

Background: The International Randomized study of Interferon versus STI571 (IRIS) study demonstrated that imatinib has superior safety and efficacy relative to interferon-α plus cytarabine (IFN+ara-C). Patients on the imatinib arm achieved an estimated 5-year OS of 89%. To monitor the long-term responses achieved by patients on imatinib, the 6-year follow-up of the IRIS patient population is summarized.Methods: 1106 patients were randomly assigned to either imatinib or IFN+ara-C and evaluated for hematologic and cytogenetic responses, event-free survival, progression to accelerated-phase (AP) or blast crisis (BC), overall survival (OS), and frequency of adverse events and discontinuations.Results: The downward trend in the risk of disease progression on imatinib has continued with a 0.4% event rate (including loss of response) and a 0% rate of transformation to AP/BC attained between years 5 and 6. Of 553 who were randomized to imatinib, 364 (65.8%) remain on study drug at 6 years: 14 (2.5%) crossed over to the IFN arm, and 175 (31.6%) pts have discontinued from imatinib study therapy for any reason. The following reasons were cited for discontinuation from the IRIS study: adverse events, 23 patients (4.2%); unsatisfactory therapeutic effect, 66 patients (11.9%); protocol violation, 15 patients (2.7%); withdrawal of consent, 32 patients (5.8%); administrative problems, 6 patients (1.1%); and 16 patients (2.9%) elected to undergo a stem cell transplantation (SCT). Death was the reason for discontinuation for 10 (1.8%) patients, and 7 patients (1.3%) were lost to follow-up. The best observed complete hematologic response rate among patients receiving first-line imatinib was 97%. The best observed major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) rates were 89% and 83%, respectively, with 2 additional CCyR observed since the prior 5-year analysis. At the current 6-year follow-up, 325 patients are still in CCyR, another 24 had lost CCyR but regained it, 6 patients lost CCyR but remain in MCyR, and the remaining 9 patients never had a documented CCyR. Overall, an estimated 83% of patients were event-free, and 93% were free of progression to AP or BC at 6 years on imatinib study treatment, as patients were followed only for OS after discontinuation. After the second year on imatinib, the annual rate of events decreased every year, as did the annual relapse rate. Based on the current follow-up, a total of 66 (12%) patients have died (19 after SCT, 27 not due to CML). Estimated 6-year OS rate for all patients who received imatinib as initial therapy was 88%. When survival is censored at time of SCT for patients who proceeded to transplant, the estimated OS at 6 years is 91%. In an analysis of serious adverse events, no new safety issues were identified between the 5-year report and this analysis.Conclusions: The 6-year follow-up analysis of the IRIS population indicates that continuous treatment of chronic-phase CML with imatinib induces durable responses in a high percentage of patients with a decreasing rate of relapse and a favorable long-term safety profile.

Dasatinib (SPRYCEL®) in Patients (pts) with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Who Are Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results from the CA180-015 ‘START-L' Study.

Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC. Relapsing pts with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) who have been previously treated with chemotherapy including im have a very poor prognosis. START-L is an open label, multi-center, global phase-II study, which treated 46 im-r or im-i pts with Ph(+) ALL from January through June 2005. Dasatinib was given orally, 70 mg twice daily (BID) with escalation to 100 mg BID for poor response or reductions to 50 mg and 40 mg BID for toxicity. Response was assessed on weekly blood counts and monthly bone marrow exams, including cytogenetics. Mutation analysis was conducted at baseline and at end of study. Quantitative PCR was carried out pretreatment and at the time of complete cytogenetic response (CCyR). At the time of this update, all 46 pts had a minimum of 9 months (mo) of follow-up. Of these, 44 (96%) were im-r; due to the small number of im-i pts, data for all pts are presented. 59% of patients were male and median age was 48 years. The median time from initial Ph(+) ALL diagnosis to first dose was 18 mo. All patients had been pretreated with im including 46% with 600 mg per day or more, and 52% whose duration of im treatment was more than 12 mo. 37% of the pts had received a stem cell transplant. At baseline, 67% of pts had WBC <2000/mm3, 74% had platelets <100 × 103/mm3, and 24% had extramedullary disease outside of the spleen. In the 40 pts with baseline mutation data, im-resistant BCR-ABL mutations were observed in 78%, one with T315I. The median duration of therapy was 3.0 mo (range 0.03–16.5) for all pts and was 13.0 mo (9.2–16.5) for pts still on study. The overall complete hematologic response rate was 35%. The major cytogenetic response was 57%, including 54% CCyR. The major hematologic response (MHR) in the 31 pts with baseline mutations was 45%. The median duration of MHR was 11 mo and the median progression-free survival was 3.7 mo (95% CI 1.6–6.1). Grades 3 and 4 thrombocytopenia occurred in 13% and 67%, respectively and grades 3 and 4 neutropenia occurred in 27% and 52% of pts, respectively. Most frequent non-hematologic toxicities included diarrhea in 30% (grade 3–4, 7%), nausea in 22% (no grade 3–4), pyrexia in 22% (grade 3–4, 2%), and pleural effusion in 22% (grade 3–4, 7%) of pts. Dose was reduced in 30% and interrupted in 43% of pts, primarily due to non-hematologic toxicities. Dasatinib has important efficacy in this Ph(+) ALL pt population. Updated efficacy (including molecular response), safety, and mutational analysis data will be presented at the meeting.

Long-term benefits of imatinib (IM) for patients newly diagnosed with chronic myelogenous leukemia in chronic phase (CML-CP): The 5-year update from the IRIS study

6506 Background: IM was proven to be superior to IFN+Ara-C for newly diagnosed patients (pts) with CML-CP (O’ Brien et al, NEJM 2003). 1,106 pts were randomized between June 2000 and Jan 2001 to either IM 400 mg or IFN+Ara-C with 553 pts to each treatment. This abstract is based on data collected up to 54 months after last patient had been recruited on IM. 60-months (5-year) data will be available for presentation. Methods: Evaluations included complete hematologic response (CHR), complete/partial cytogenetic response (CCyR/PCyR - defined as 0% / 1–35% Ph+ metaphases respectively), major cytogenetic response (MCyR=CCyR+ PCyR), major molecular response (MMR) - defined as ≥ 3 log reduction of BCR-ABL transcript levels from the standardized baseline, time to progression - defined as loss of CHR/MCyR, evolution to accelerated phase/blast crisis (AP/BC), or death due to any cause during treatment, and overall survival. Results: With a median follow-up of 54-months, 72% of the 553 randomized pts remain on initial IM treatment (5% of pts discontinued due to adverse events, 9.5% due to unsatisfactory therapeutic effect and 11% due to other reasons another 2.5% crossed over to IFN+Ara-C). Overall, the cumulative best response rates of CHR, MCyR and CCyR are 97%, 88% and 82%, respectively. The overall estimated survival was 90% (93% when censored at bone marrow transplant). An estimated 84% of pts have not progressed on treatment and 93% of pts were free from progression to AP/BC. The annual rate of progression to AP/BC of &lt; 1% in the fourth year was lower than each of the first three years (1.5, 2.8, and 1.6%, respectively). Of the pts with MCyR at 12 months (n=436), an estimated 96% were free of progression to AP/BC at 54 months whereas it was only 81% for the 73 pts who did not achieve a MCyR at 12 months (p&lt; 0.001). No patient with a MMR within 12 months progressed to AP/BC within 54 months. Conclusions: This analysis confirms the high rates and durability of responses to IM. Encouragingly, the rate of progression in the fourth year was lower than in each of the preceding three years. Results further demonstrate the beneficial effect of cytogenetic and molecular responses on long-term outcomes. [Table: see text]

Dasatinib (BMS-354825) in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Who Are Resistant or Intolerant to Imatinib: Update of a Phase I Study.

Imatinib mesylate resistance in CML and Ph+ ALL is frequently associated with BCR-ABL mutations that interfere with the ability of imatinib to inhibit BCR-ABL. Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor, which targets BCR-ABL and SRC kinases. Dasatinib is 325-fold more potent versus imatinib in cells transduced with wild-type BCR-ABL, and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutants (O'Hare, et al. Cancer Res 65(11):4500–5, 2005; Shah et al, Science , 305:399–401, 2004). Here we present an update of a Phase I dose-escalating study, initiated in November 2003, of dasatinib in imatinib-resistant/intolerant patients with CML in late chronic phase (CP) or advanced disease (accelerated phase [AP], myeloid blast crisis [MBC] or lymphoid blast crisis [LBC]) or with Ph+ ALL. Data are available for 84 patients (40 CP, 10 AP, 23 MBC, 11 LBC/Ph+ ALL). As of this writing, 40 CP patients, with 8 years' median duration of CML (range: 1–17 yrs), have been treated with dasatinib (15–180 mg/day, once-daily [QD] or twice daily [BID]) for a median of 13 months. The rate of complete hematologic response (CHR) in CP is 88% (35/40). Major cytogenetic responses (MCyR) were observed in 40% (16/40), with complete CyR (CCyR) in 33% (13/40). In advanced disease, 44 patients have been treated with dasatinib (70–240 mg/day, BID) for a median of 3–7 months, depending on the cohort (see Table); 2 patients (1 MBC and 1 LBC) are not evaluable for response, but are included in the analysis of time to progression. The rate of major hematologic response (MHR) (bone marrow blasts <5%) is 80% (8/10) in AP, 77% (17/22) in MBC and 60% (6/10) in LBC/Ph+ ALL. The CHR rate (<5% bone marrow blasts, with recovery of peripheral blood counts) is 50% (5/10) in AP, 18% (4/22) in MBC and 50% (5/10) in LBC/Ph+ ALL. The overall rates of MCyR and CCyR in advanced disease were 36% (15/42) and 21% (9/42), respectively. Cytogenetic responses were seen in patients with a wide spectrum of BCR-ABL mutations, as well as in patients with minimal or no prior CyR with imatinib. Treatment was well tolerated. Reversible grade 3–4 myelosuppression was observed in all cohorts [CP (38%); AP (70%); MBC and LBC/Ph+ ALL (91%)]. 8 patients developed unexplained pleural effusions (2 CP; 6 BC), which were easily managed without treatment discontinuation. No patients have gone off study for toxicity. Responses are durable in CP and AP patients, but relapses have occurred in the MBC and LBC/Ph+ ALL cohorts, often due to dasatinib-resistant BCR-ABL mutations. These data support the therapeutic potential of dasatinib in patients with imatinib-resistant or -intolerant CML/Ph+ ALL. Phase II studies (the ‘START' [SRC/ABL Tyrosine kinase inhibition Activity: Research Trials of dasatinib] program) are currently ongoing in imatinib-resistant/intolerant patients with all phases of CML and Ph+ ALL.Phase of CML/ALLPatients remaining in response at July 31, 2005Follow-up, median (range) daysCP (N=40)36 (90%)392 (95–588)AP (N=10)8 (80%)200 (39–365)MBC (N=23)9 (39%)144 (2–364)LBC/Ph+ ALL (N=11)1 (9%)77 (8–233)

Imatinib 800 mg: Preliminary Results of a Phase II Trial of the GIMEMA CML Working Party in Intermediate Sokal Risk Patients and Status-of-the-Art of an Ongoing Multinational, Prospective Randomized Trial of Imatinib Standard Dose (400 mg Daily) vs High Dose (800 mg Daily) in High Sokal Risk Patients.

The conventional treatment of chronic myeloid leukemia (CML) in early chronic phase (ECP) is imatinib 400 mg daily. The estimated rates of major (MCgR) and complete cytogenetic response (CCgR) at 42 months are 91% and 84%, respectively (IRIS Trial - F Guilhot, ASH 2004), with a survival free from accelerated and blastic phase of 84%. The rates of CCgR are significantly different according to Sokal score, being 91%, 84% and 69% for low, intermediate and high risk categories. Phase I and II trials of imatinib have clearly shown a dose-response effect; more importantly, a single center phase II trial of imatinib 800 mg in ECP showed significantly better results vs standard dose, in terms of CCgR (90% vs 74%) and of complete molecular response (28% vs 7% at 18 months) [H. Kantarjian et al, Blood 103 (8), 2004]. The GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) CML WP is conducting a phase II trial of imatinib 800 mg in intermediate Sokal risk in ECP (trial CML/021). Overall, 89 pts (mean age 53 yrs) have been enrolled. Fourty-four patients completed 6 months of treatment: the complete hematological response rate is 100%; the MCgR and CCgR are 90% and 81%, respectively. The 6 months CCgR rate of this trial parallels the IRIS trial one in intermediate risk cases (84%), with a much shorter treatment period. The major molecular response rate at 6 months (RTQ-PCR as ratio BCR-ABL/ABL) is 56% (cut-off ≤ 0.12%) or 41% (cut-off ≤0.05%). The compliance to the treatment improved time by time, being 47% the patients receiving ≥ 80% of the scheduled dose between months 1–3 and 60% between months 4 - 6. A second project, exploring imatinib high dose, is reserved to high risk cases: a multinational working group, within the frame of Leukemianet CML WP, is conducting a phase III randomized trial (1:1) of imatinib 400 mg vs 800 mg in high Sokal risk in ECP. By July 31, 2005, 80 patients have been enrolled: GIMEMA CML WP (44 pts), Nordic Countries - Sweden, Denmark, Norway and Finland (25 pts), Turkey (10 pts) and Israel (1 pt).

Survival benefit with imatinib mesylate therapy in patients with accelerated‐phase chronic myelogenous leukemia—Comparison with historic experience

The effect of imatinib mesylate on survival in the accelerated phase of chronic myelogenous leukemia (CML) is unknown. The objectives of this study were to update the long-term experience with imatinib in patients who had accelerated-phase CML and to compare outcomes with historic experience. The outcomes of 176 patients who received treatment with imatinib were reviewed and compared with the outcomes of 213 historic control patients with accelerated-phase CML who received treatment with interferon-alpha or with other modalities. With imatinib, the complete hematologic response rate was 82% versus a rate < or = 50% for others, and the complete cytogenetic response rate was 43% versus rates of 0-6% for others. The estimated 4-year survival rates were 53% with imatinib, 42% with interferon-alpha, and 0-21% for others. A multivariate analysis of the total population of 389 patients indicated that imatinib therapy (vs. other therapies) was an independent, favorable prognostic factor for survival (P < 0.0001; hazard rate, 0.62). A subset analysis that included only patients who were treated with imatinib and interferon-alpha (276 patients) also identified imatinib as an independent favorable prognostic factor (P < 0.0001; hazard rate, 0.65). The 3-month cytogenetic response to imatinib was associated with significantly different survival outcomes (P < 0.0001). A multivariate analysis that included pretreatment characteristics and 3-month cytogenetic response among 150 patients who received imatinib and were alive at 3 months identified only 2 adverse independent prognostic factors: lack of a cytogenetic response at 3 months (P < 0.001) and anemia (hemoglobin < 10 g/dL; P = 0.003). Patients who had neither factor (41%) had an estimated 4-year survival rate of 88%; in the other patients, the 4-year survival rate was < or = 60%. This may have implications in relation to subsequent therapy, because, according to the outcomes of patients who underwent allogeneic transplantation in accelerated phase at the authors' institution and from literature reports, the estimates of 5-year survival were 25-30%. The current results suggest that imatinib improved survival compared with other therapies in patients with accelerated-phase CML.

Survival Advantage for Patients (pts) with Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP) Treated with Imatinib.

When treated with imatinib, pts with CML in AP have a hematologic response rate of over 80%, and 25% achieve a major cytogenetic (CG) response. These results are superior to any other therapy available and have established imatinib as the standard of care for AP CML. However, a survival benefit was not defined in these single-arm studies. With longer follow-up of pts in AP treated with imatinib, we investigated whether imatinib therapy led to a survival advantage over other therapies that have been used for this disease. For this analysis, AP was defined as the presence of any of the following: blasts ≥15%, blasts + promyelocytes ≥30%, basophils ≥20%, platelets (plts) <100 x109/L unrelated to therapy, or clonal evolution. Since 1982, 395 pts with AP have been treated at MDACC: 177 (45%) with imatinib and 218 (55%) with other therapies including IFN-α-based therapy (n=102), homoharringtonine (n=36), decitabine (n=47), daunorubicin + ara −C (n=24), or others (n=9). The rate of complete hematologic response was 82% with imatinib and 38% with others (p < 0.0001), and major cytogenetic response was 48% and 13%, respectively (p <0.0001). The median follow-up is 41 months (mo) (range, 3 – 206): 38 mo (3 to 63) for the imatinib group and 82 mo (3 to 206) for the others. A total of 249 pts have died: 67 in the imatinib cohort and 182 in the control group. The median survival was 21 months for the control group, and has not been reached for the imatinib cohort (estimated rate 53% at 3 yrs). Clinical characteristics adversely affecting survival (p<0.05) included time from diagnosis to treatment >36 mo, splenomegaly, Hgb <10 g/dl, plts <100 x109/L, peripheral or marrow blasts ≥5%, marrow basophils >5%, blasts + promyelocytes >5%, clonal evolution, and treatment with imatinib. Pts treated with imatinib were older, but had fewer pts with splenomegaly, high blasts or clonal evolution than the control group. By multivariate analysis, the independent pre-treatment characteristics associated with survival (p<0.05) were splenomegaly, anemia, presence of peripheral blood blasts, and disease duration >1 yr. After adjusting for these differences in a multivariate analysis, treatment with imatinib was the most significant prognostic factor associated with improved survival (p<0.0001). We conclude that treatment with imatinib has changed the natural history of AP CML with an expected median survival in excess of 3 years.

Excessive Weight Gain during Mobilization Increases First Year Mortality Following High Dose Therapy and Stem Cell Transplantation in Patients with Primary Amyloidosis.

Introduction: High dose melphalan followed by stem cell transplantation (HDM-SCT) is currently the most effective therapy for primary systemic (AL) amyloidosis. Recent data showed a 40% complete hematologic response rate and median survival of 4.6 years with HDM-SCT can be obtained. Despite its advantages, treatment mortality can be excessive in high-risk patients. Previously, extensive cardiac, hepatic or renal involvement had been identified as risk factors for poor outcome. We observed that patients who had more than 2% weight gain during mobilization also had a poorer survival after HDM-SCT. This study was undertaken to further examine the outcome of these patients.Patients: Consecutive patients who underwent HDM-SCT for AL between 7/97 and 6/04 were retrospectively studied. Weight (kg) was measured just prior to mobilization, at its peak during mobilization and collection, and just prior to conditioning. Baseline characteristics were extracted from medical records along with left ventricular ejection fraction (LVEF), septal thickness, glomerular filtration rate (GFR), proteinuria, alkaline phosphatase, and the number of visceral organ involved with AL. Mobilization was achieved by cyclophosphamide (C) with granulocyte colony growth factor (GCSF), C with granulocyte-macrophage colony stimulating factor (GMCSF), GCSF alone and GMCSF alone or in combination with GCSF. Patients were conditioned with melphalan in doses of 100mg, 140mg or 200mg per m2 or 140 mg/m2 in combination with total body irradiation. Hematologic response was determined by A 50% reduction in measurable monoclonal protein levels or complete eradication by immunofixation if too small to quantify.Results: During the time period, 128 patients underwent HDM-SCT for AL. One patient was excluded because no weight was recorded during mobilization and 1 refused consent. Weight gain of 2% or greater was noted in 51.6% (65) of the patients. Mortality at 1 year was significantly higher in patients with > 2% weight gain (32.3%) compared to those without (9.8%) (OR = 4.37, 95% CI 1.71 to 12.77, p = 0.004). Univariate analysis identified septal thickness, GFR, alkaline phosphatase, organ involvement and weight gain as risk factors of mortality at 1 year. Using the logistic model, only septal thickness (p =0.04), GFR (p = 0.009) and weight gain (p = 0.009) remained independent predictors of first year mortality in the multivariate analysis. No association was found between weight gain and mobilization regimen. Analysis of patient who survived the first 100 days posttransplant showed no correlation between weight gain and hematologic response. Finally, weight reduction to baseline prior to conditioning did not improve first year survival for those who gained > 2% during conditioning.Conclusion: Our study found weight gain of 2% or more was associated with significantly higher first year mortality after HDM-SCT. The effect of weight gain was independent of both cardiac and renal involvement with AL. Fluid retention was not directly responsible for the higher mortality, as weight reduction to baseline failed to improve the outcome of these patients. Weight gain during mobilization appears to be a novel pretransplant risk factor that predicts the outcome of HDM-SCT based on response to mobilization.

The Role of Imatinib in the Treatment of Chronic Myelogenous Leukemia

The Philadelphia chromosome and resultant Bcr-Abl fusion protein define most cases of chronic myelogenous leukemia (CML). The characterization of this protein and its integral role in the pathogenesis of leukemia has led to the development of specific inhibitors of Bcr-Abl which possess potent anti-tumor activity both in vitro and in vivo. Imatinib, the only widely available Bcr-Abl inhibitor, represents the paradigm for rational drug development in the treatment of malignancies. It is highly effective in the treatment of chronic phase CML disease, producing a 95% complete hematologic response rate in interferon (IFN)-resistant patients. In contrast to IFN-based therapy, the majority of patients on imatinib will achieve a major cytogenetic response, suggesting a potential survival benefit. Imatinib also has a significantly more favorable toxicity profile than IFN or transplant-based strategies. Importantly, progression to the accelerated or blastic phases of the disease is rare in patients responding to imatinib. On the basis of these findings, the majority of patients with chronic phase CML should be considered for a trial of therapy with imatinib, either in the clinic or in the context of a clinical trial. Failure to achieve a complete hematologic response within 3 months or a cytogenetic response within 6 months should lead to consideration of allogeneic transplantation, IFN therapy or participation in available clinical trials. While a substantial proportion of patients with accelerated or blastic phase disease will have a response to imatinib, these responses are transient with eventual resistance as the rule. Therefore, single-agent treatment with imatinib in this setting is not recommended unless it is used as a bridge to more definitive therapy such as transplantation.

Anagrelide and imatinib mesylate combination therapy in patients with chronic myeloproliferative disorders.

The tyrosine kinase inhibitor imatinib mesylate inhibits the function of the Bcr-Abl oncoprotein associated with Philadelphia-positive chronic myelogenous leukemia (CML). Anagrelide suppresses megakaryocyte proliferation and differentiation. The objectives of this study were to investigate the feasibility and safety of imatinib mesylate and anagrelide combination therapy in patients with Ph-positive CML or chronic myeloproliferative disorders (MPD) with persistent thrombocythemia. This study was a retrospective review of all available records of patients with chronic MPD presenting to the M.D. Anderson Cancer Center between October 1998 and May 2002, treated with imatinib mesylate combined with anagrelide. Of 22 patients identified, 18 had Ph-positive CML (chronic phase, 16 patients; accelerated phase, 2 patients), 1 had agnogenic myeloid metaplasia (AMM), 2 had essential thrombocythemia (ET) and 1 had MPD transformed into refractory anemia with excess blasts (RAEB). The median age was 57 years (range 26-82 years). The median dose of imatinib mesylate administered was 400 mg (range 300-800 mg) and the median dose of anagrelide was 1.5 mg (range 0.5-4.0 mg). Imatinib mesylate and anagrelide combination therapy was feasible and tolerable. Of the 18 patients with Ph-positive CML, 15 in chronic phase and 1 in accelerated phase achieved a complete hematologic response (CHR), and 9 of the 18 achieved cytogenetic response (complete in 8 patients). No responses were noted in patients with AMM, ET or MPD transformed into RAEB. The combination of imatinib mesylate and anagrelide was safe and was associated with an 89% CHR rate in patients with CML in chronic phase and persistent thrombocythemia.

Prognosis and prognostic factors for patients with chronic myeloid leukemia: Nontransplant therapy

Reliable knowledge about an individual's prognosis is needed to select the appropriate treatment for patients with chronic myeloid leukemia (CML). The New CML score using age, spleen size, blast cell count, eosinophil count, basophil count, and platelet count shows good discrimination for survival (96, 65, or 42 months, P ≤ .0001) and has been thoroughly validated. Careful analyses indicate that the New CML score is considerably more precise in identifying high-risk patients than the Sokal score. Achievement of complete hematologic response (CHR) up to 9 months shows a distinct impact on survival, which, however, depends on the baseline prognosis. Ten-year survival probabilities for low- and intermediate-risk patients with a CHR were 0.51 (95% confidence interval [CI], 0.42 to 0.60) and 0.23 (95% CI, 0.15 to 0.31) and without a CHR were 0.26 (95% CI, 0.16 to 0.37) and 0.12 (95% CI, 0.04 to 0.20). In high-risk patients CHR had no impact on prognosis. Therapeutic options were widened by the approval of imatinib for the treatment of CML. However, it will still take 2 or more years to know whether the high rates of CHR and cytogenetic complete remission (CCR) achieved with imatinib translate into a clinically relevant survival advantage for all patients. Semin Hematol 40:4-12. Copyright 2003, Elsevier Science (USA). All rights reserved.

Prognosis and prognostic factors for patients with chronic myeloid leukemia: nontransplant therapy.

Reliable knowledge about an individual's prognosis is needed to select the appropriate treatment for patients with chronic myeloid leukemia (CML). The New CML score using age, spleen size, blast cell count, eosinophil count, basophil count, and platelet count shows good discrimination for survival (96, 65, or 42 months, P </=.0001) and has been thoroughly validated. Careful analyses indicate that the New CML score is considerably more precise in identifying high-risk patients than the Sokal score. Achievement of complete hematologic response (CHR) up to 9 months shows a distinct impact on survival, which, however, depends on the baseline prognosis. Ten-year survival probabilities for low- and intermediate-risk patients with a CHR were 0.51 (95% confidence interval [CI], 0.42 to 0.60) and 0.23 (95% CI, 0.15 to 0.31) and without a CHR were 0.26 (95% CI, 0.16 to 0.37) and 0.12 (95% CI, 0.04 to 0.20). In high-risk patients CHR had no impact on prognosis. Therapeutic options were widened by the approval of imatinib for the treatment of CML. However, it will still take 2 or more years to know whether the high rates of CHR and cytogenetic complete remission (CCR) achieved with imatinib translate into a clinically relevant survival advantage for all patients.

Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia

Twenty-eight adults with chronic myelogenous leukemia (CML) that had relapsed after allogeneic stem cell transplantation (SCT) received imatinib mesylate (400-1000 mg/d). Disease was in chronic phase in 5 patients, accelerated in 15, and blastic in 8 (7 medullary, 1 extramedullary); median time from transplantation to relapse was 9 months (range, 1-137 months). Thirteen patients had undergone salvage donor lymphocyte infusion (DLI) (median time from DLI to imatinib mesylate therapy, 4 months [range, 2-39 months]). The overall response rate was 79% (22 of 28 patients); the complete hematologic response (CHR) rate was 74% (17 of 23 patients), and the cytogenetic response rate was 58% (15 of 26 patients; complete response in 9 [35%] patients). CHR rates were 100% for chronic phase, 83% for accelerated phase, and 43% for blastic phase. The patient with extramedullary blastic disease achieved complete response. Cytogenetic response rates were 63% (12 of 19 patients) for chronic or accelerated phases (complete cytogenetic response in 8) and 43% for blastic phase (3 of 7 patients). At median follow-up of 15 months, 19 patients were alive, 9 with no evidence of disease. The 1-year estimated survival rate was 74%. Five patients had recurrence of grade 3 (3 patients) or grades 1 to 2 (2 patients) graft-versus-host disease (GVHD). Severe granulocytopenia developed in 43% of patients and thrombocytopenia in 27%; both conditions reversed with dose adjustments of imatinib mesylate. We conclude that imatinib mesylate effectively controlled CML that recurred after allogeneic SCT, but it was associated with side effects including myelosuppression and recurrence of severe GVHD.

Simultaneous homoharringtonine and interferon-alpha in the treatment of patients with chronic-phase chronic myelogenous leukemia.

Homoharringtonine (HHT) has antileukemic activity in patients with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML). Combinations of HHT, interferon-alpha (IFN-alpha), and cytarabine (ara-C) have been studied in various CML phases. The objectives of this study were to evaluate the efficacy and toxicity profiles of a combination regimen of simultaneous HHT and IFN-alpha therapy in patients with chronic-phase CML who were not exposed previously to either agent. Forty-seven patients were treated: 37 patients with early chronic-phase CML (2 patients with clonal evolution) and 10 patients with late chronic-phase CML. Their median age was 62 years (range, 23-73 years). HHT was given at a dose of 2.5 mg/m(2) by continuous intravenous infusion over 24 hours daily for 5 days every month, and IFN-alpha was given daily at a target dose of 5 x 10(6) units/m(2) subcutaneously. Response, survival, and treatment toxicity were analyzed. Overall, the complete hematologic response (CHR) rate was 85%; the cytogenetic response rate was 66%, with major cytogenetic responses (Ph positive in < 35% of metaphases) in 49% of patients and complete cytogenetic responses in 21% of patients. The CHR rate, cytogenetic response rate, and major cytogenetic response rate were 84%, 69%, and 52%, respectively, in patients with early chronic-phase CML. Among the 10 patients with late chronic-phase CML, the CHR rate, cytogenetic response rate, and major cytogenetic response rate were 80%, 50%, and 40%, respectively. Response rates in patients age > 60 years were 84%, 62%, and 49% for CHR, cytogenetic response, and major cytogenetic response. Myelosuppression was frequent but manageable: Anemia with hemoglobin < 8.0 g/dL occurred in 36% of patients, requiring dose adjustments and erythropoietin therapy. Nonhematologic toxicities were mainly fatigue, aches, and gastrointestinal disturbances. Dose reductions with multiple courses were significant and were due to myelosuppression: After 6-24 courses, the median daily IFN-alpha dose was 1 MU/m(2), and the median number of days on HHT per month was 2 days. With a median follow-up of 26 months, the estimated 2-year survival rate was 90% (95% confidence interval, 79-100%). The simultaneous combination of HHT and IFN-alpha is safe and effective, but the dose schedules that actually were delivered were significantly lower than the planned dose schedules. With the availability of signal-transduction inhibitor 571 (imatinib mesylate), studies of combination of HHT and IFN-alpha chemotherapy in patients with CML who have disease that fails to respond to imatinib mesylate and of combinations with imatinib mesylate need to be explored.

A randomized study of interferon-α versus interferon-α and low-dose arabinosyl cytosine in chronic myeloid leukemia

Interferon-alpha (IFN-alpha) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-alpha has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome-positive CML patients who were assigned at random to treatment with IFN-alpha 2a alone or in combination with LDAC. The scheduled dose of IFN-alpha 2a was 5(6) IU/m(2)/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-alpha-plus-LDAC arm versus 55% in the IFN-alpha arm; P =.11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P =.003), and overall survival (5-year survival, 68% versus 65%; P =.77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-alpha versus IFN-alpha plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.

Unexpected High Incidence of Severe Toxicities Associated with Alpha Interferon, Low-Dose Cytosine Arabinoside and All-Trans Retinoic Acid in Patients with Chronic Myelogenous Leukemia

Preclinical data have shown that all-trans retinoic acid (ATRA) with interferon-alpha (IFN-α) can exert significant suppressive effects on Philadelphia-chromosome (Ph)-positive cells. The aim of this study combining IFN-α, low-dose cytosine arabinoside (ara-C) and ATRA was to increase the proportion of patients achieving a major cytogenetic response, in comparison with a group of 140 patients previously treated with IFN-α plus low-dose ara-C. Forty three patients with Ph-positive CML in early chronic phase were treated with IFN-α 5 MU/m2 sc daily, low-dose ara-C 10 mg sc daily and ATRA 45 mg/m2orally daily, for 7 consecutive days every other week. Overall, 76% of patients achieved a complete hematologic response (CHR). A cytogenetic response was in observed 59% (major in 38% and complete in 17%). Compared with patients treated with IFN-α and low-dose ara-C, those receiving additional ATRA had a lower CHR rate (p. 014), but other response rates were similar. Severe toxicities were common with the triple regimen (64%), mostly related to ATRA therapy. Two patients experienced pseudotumor cerebri; two patients had leukocytosis during the week on ATRA treatment, decreasing during the week off (one suffered a severe asthma-like reaction followed by pulmonary edema, resembling ATRA syndrome). Six patients had other unusual side-effects: aseptic necrosis of the hip (1 patient), ataxic syndrome (1 patient), paranoid syndrome (2 patients), syncopal episodes (1 patient), pure red cell aplasia (1 patient). In conclusion the results of IFN-α and low-dose ara-C combined with ATRA in patients with early CML-chronic phase were disappointing, due to excessive toxicity. Whether different ATRA dose schedules may result in fewer side-effects and improve hematologic and cytogenetic response remains to be determined.

Interferon alpha‐2b as therapy for patients with Ph‘‐positive chronic myelogenous leukemia

We treated 114 Ph'+ chronic myeloid leukemia (CML) patients, 105 of whom were in chronic phase (CP) and 9 in accelerated phase (AP), with interferon alpha-2b (IFN alpha-2b) at intermittent or daily doses of 2-5 MU/m2. Of 35 previously untreated CP patients, 22 (63%) showed complete hematological response (CHR). This was significantly influenced by initial risk status. In 19 of the 22 CHR patients the median of Ph'+ cells decreased from 100% to 58%. Of 36 patients pretreated for less than 12 months, 19 (53%) achieved CHR. CHR rate was significantly related to IFN dose. Cytogenetic improvement was observed in 15 of the 19 patients, the median of Ph'+ cells dropping from 100% to 76%, with complete suppression of the Ph' chromosome in 1 case. Of the 34 patients pretreated for greater than 12 months, 21 (62%) obtained CHR. Cytogenetic improvement was observed in 10 cases, the median of Ph'+ cells declining from 100% to 66%. 1 of 9 AP patients obtained CHR. After a median follow-up of 32 months for the 63 CHR patients, 49 (78%) are still in disease control: 34 on IFN therapy, 15 after bone marrow transplantation (BMT) (13 autologous and 2 allogeneic). Blastic transformation (BT) occurred in 9 of 63 (14%) CHR patients and in 24 of 51 (47%) patients with less than CHR. IFN alpha-2b has proved to be an effective treatment for CML. Its combination with other treatment modalities represents an interesting and promising approach for future studies.