Ash Conference 2007 Abstracts

A selection of abstracts from ASH 2007 are listed below. Jan Giessler of Leukemie-online.de and the CML Advocates Network compiled the following list. I would like to thank Jan for his generosity in sharing this with us.

[#28] Sustained Molecular Responses with Interferon-2a Maintenance Therapy after Imatinib Plus IFN Induction Treatment for Chronic Phase CML

A recent study from Mannheim on report a high rate of improved or continuous molecular remissions in 17 of 20 patients (85%) on IFN monotherapy after prior induction with IM/IFN. This suggests a previously unrecognized beneficial role for IFN in the maintenance therapy after IM-mediated debulking and may impact future CML therapy. Most patients with chronic myelogenous leukaemia (CML) relapse after discontinuation of imatinib (IM, Glivec/Gleevec). Thus, current recommendations suggest a lifelong IM therapy even in complete molecular responders. However, in view of potential long-term adverse effects there is a concern of tyrosine kinase inhibition. Hence, strategies to circumvent permanent kinase inhibitor therapy would be of substantial clinical value.

Interferon (IFN), in contrast to IM, elicits an autologous anti-leukaemic immune response to control CML, and stopping IFN in complete cytogenetic responders is not associated with relapse in a significant proportion of patients. We therefore sought to determine efficacy and tolerability of an IFN maintenance immunotherapy after IM/IFN induction in newly diagnosed chronic phase CML patients. Twenty patients (14 m, 6 f; median age 44.6, range 23.5-74.1 years) have been investigated.

Hasford score revealed low (n=13), intermediate (n=6), and high risk (n=1) diseases. IM therapy had been administered for 2.4 yrs (0.2-4.9), combined with PEG-IFN2a (Pegasys, n=17) or IFN2a (Roferon, n=3). Maintenance therapy consisted of PEG-IFN (n=16) or IFN (n=4). Dose was adjusted according to response and tolerability and ranged between 135 g PEG-IFN every three weeks to 180 g PEG-IFN once weekly week, or alternatively between 2 to 5*3 Mill IU IFN/week. IM was stopped due to side effects (n=5) or after the patient’s individual request and informed consent (n=15). At the time of imatinib withdrawal, 19 patients were in complete cytogenetic remission and one patient did not show any cytogenetic response. Major molecular response was determined in peripheral blood leukocytes of 16 patients, including one patient with undetectable BCR-ABL transcripts. After a median observation time of 1.2 yrs (range 0.1-3.1), 15 patients showed major molecular response, seven of them were complete.

Improvement of molecular response was observed in seven and a stable situation in ten patients. By 6 weekly assessments of BCR-ABL expression gradual molecular relapse was observed in three patients. All relapsing patients responded to re-administration of IM. At the time of IM withdrawal and during IFN maintenance therapy myeloblastin (proteinase-3, PR3) mRNA expression was determined and compared to glucose-6-phosphate dehydrogenase transcripts as internal standard. During IFN monotherapy, median ratios PR3/G6PD increased from 0.06% (range, 0.02-3.5) to 0.14% (0.03-1.4; p=0.03). IFN response was associated with the detection of autoreactive PR3 specific T-lymphocytes during IFN maintenance therapy determined by a tetramer assay in 7/8 patients, suggesting that PR3-specific cytotoxic T lymphocytes contribute to the IFN-mediated anti-leukaemic immunity.

In conclusion, we report a high rate of improved or continuous molecular remissions in 17 of 20 patients (85%) on IFN mono-therapy after prior induction with IM/IFN. This suggests a previously unrecognized beneficial role for IFN in the maintenance therapy after IM-mediated de-bulking and may impact future CML therapy.

Andreas Hochhaus et al, Germany

[#25] IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation

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 favourable long-term safety profile. The International Randomized study of Interferon versus STI571 (IRIS) study demonstrated that imatinib has superior safety and efficacy relative to interferon 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.

Andreas Hochhaus, Brian J. Druker, Richard A. Larson, Stephen G. O'Brien, Insa Gathmann, Francois Guilhot

Abstract #25 - Blood, Volume 110, issue 11, November 16, 2007

[#27] Time to Complete Cytogenetic Response (CCyR) Does Not Affect Long-Term Outcomes for Patients on Imatinib Therapy.

Long-term outcomes on imatinib for patients in CML-CP are independent of time to achieve CCyR. Therefore, achievement of a late CCyR does not increase the potential for progression or portend a worse overall survival for patients treated with imatinib.

Background: Results from the International Randomized Study of Interferon and STI571 (IRIS) trial showed that achievement of a CCyR is prognostically relevant for long-term survival in patients (pts) with CML in chronic phase (CML-CP). With the advent of next generation tyrosine kinase inhibitors (TKIs), there is a need to understand factors that may influence long-term outcomes. Here we analyze whether time to achievement of a CCyR affects long-term outcomes.

Results: In the 447 patients who were treated for at least 1 year and achieved a CCyR (<1% Ph+) during therapy, the durability of major cytogenetic response (1%-35% Ph+) did not differ significantly regardless of when CCyR was achieved (P=0.76). For the overall population, estimated 6-year rates were 88% for OS, 83% for EFS, and 93% for freedom from progression to AP/BC. No statistically significant difference was observed between the responders when categorized according to time to response. However, patients who did not achieve a CCyR had significantly worse outcomes than those who achieved CCyR (P<0.001).

Estimated 6-year OS rates were 94%, 95%, 91% and 98% for patients who first achieved a CCyR within 6, 12, 18 months and after 18 months, respectively compared with 63% for pts without CCyR during imatinib therapy. Estimated EFS rates at 6 years were 93%, 90%, 87% and 89% (P=0.58) and 33% for patients who do not achieve a CCyR, respectively. At 6 years the estimated rates of freedom from progression to AP/BC were 97%, 97%, 97% and 98%, respectively, but only 63% for pts who do not achieve a CCyR.

Francois Guilhot, Richard A. Larson, Stephen G. O'Brien, Insa Gathmann, Brian J. Druker

Abstract #27 - Blood, Volume 110, issue 11, November 16, 2007

[#1935] Imatinib Plasma Concentration and Sokal Risk Score Are Independently Prognostic for Complete Cytogenetic Response (CCyR) in Patients with Chronic-Phase CML

Results of a study of Imatinib (IM) plasma levels suggest that achieving an adequate plasma level is important for a good clinical response. Monitoring of IM plasma concentrations should be encouraged in patients with poor response. The research team analyzed the IM pharmacokinetic (PK) exposure and evaluated its effect on efficacy and safety parameters. A multivariate analysis was performed to examine whether IM plasma levels are prognostic for ability to achieve a CCyR independently of Sokal risk group, patient demographics, and laboratory data.

Results: Of 351 pts, 105 (30%) have discontinued imatinib therapy: 41% of pts with low IM trough levels (Q1), and 23% with high levels (Q4). Unsatisfactory therapeutic effect was the most frequently cited reason for discontinuation. Fluid retention, rash, myalgia, and anaemia were more frequent relevant AEs, of any grade, among pts in patients with high trough levels, but these events did not translate into significantly higher discontinuations due to AEs. Muscle cramps, diarrhoea, abdominal pain, headache, and haemorrhage were less frequent among pts with highest IM trough levels vs those with the lowest, suggesting that some AEs may be disease related. Overall, CCyR rates were 76% in pts with lowest IM trough levels (Q1), 85% in pts with intermediate levels (Q2-Q3), and 92% in pts with the highest trough levels (Q4).

Of all the evaluated prognostic variables, only Sokal risk and IM trough plasma level were prognostic for ability to achieve a CCyR. Based on the final multivariate model, for an increase by one Sokal risk level, the odds ratio of achieving a CCyR was 0.55 (95% CI, 0.32-0.93, P=0.027), while an increase by 250 ng/mL in IM trough yielded an odds ratio of 1.77 (1.22-2.56, P=0.003). No other factors met the selection criteria to remain in the final model.

Richard A. Larson, Brian J. Druker, Francois Guilhot, Stephen G. O'Brien, Tillman Krahnke, Insa Gathmann, Yanfeng Wang

Abstract #1935 - Blood, Volume 110, issue 11, November 16, 2007

[#1047] Imatinib Dose Escalation Is Effective in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP.

IM 400 mg/d is the standard of care for newly diagnosed CML. IM dose escalation to 600 and/or 800 mg allows poorly responding patients to achieve a clinically important durable response or re-gain responses. These slower responding or progressing patients benefited from IM dose escalation and thus, the data support dose escalation for these patients. Dose escalation to 600 or 800 mg IM has been shown to be beneficial in patients with either an inadequate response or disease progression while on standard therapy (Kantarjian et al Blood 2003). In the IRIS trial, dose escalation was allowed for patients who did not achieve a complete hematologic response (CHR) by 3 months or a minor cytogenetic response (minCyR) by 12 months, lost a major cytogenetic response (MCyR) at any time, or progressed (including increase in WBC); no dose escalation in cases of loss of CCyR were specified. The impact of IM dose escalation for patients on IRIS is presented in this post-hoc analysis.

Of 551 patients receiving first line IM, 106 pts (19%) had dose escalation to 600-800 mg/d. Median time to dose escalation was 22 months. After dose escalation the median imatinib dose delivered was 604 mg/d (range: 294-800 mg/d) and remained on treatment for a median of 19.4 months based on current follow-up. Last recorded dose was 600mg/d in 85% of these patients.

Responses among these patients included: 6 of 7 who had not achieved CHR at 3 months achieved a CHR with dose escalation, 2 of these patients subsequently achieved a CCyR. Of 8 patients who had not achieved a minCyR at 12 months, 4 improved to a CCyR, and of 18 patients who lost their MCyR, 9 subsequently re-achieved an MCyR within 12.5 months after dose escalation, of whom 3 also attained a CCyR by 30-months after dose escalation. The 6 patients, who received dose escalations upon progression, had an OS of 83% at 2 years after dose escalation. At 36-months after dose escalation the 39 patients dose escalated achieved an estimated PFS and OS of 81%. At 36-months follow-up after dose escalation these 48 patients achieved a 90% PFS and 89% OS. For the entire cohort of 106 patients who were dose escalated, estimated PFS was 89% and OS was 84% at 36 months after dose escalation.

Hagop M. Kantarjian, Brian J. Druker, Francois Guilhot, Jorge Cortes, Stephen G. O'Brien, Tillmann Krahnke, Richard A. Larson

Abstract #1047 - Blood, Volume 110, issue 11, November 16, 2007

[#4] Improved Early Event Free Survival (EFS) in Children with Ph+ALL with Intensive Imatinib in Combination with High Dose Chemotherapy.

Ph+ ALL remains one of the highest risk subsets of childhood ALL. A study revealed that imatinib given in combination with intensive chemotherapy resulted in a significant improvement in early EFS and reduction in early MRD. Post BMT imatinib also improved early outcome in related donor BMT. Intensive imatinib with intensive chemotherapy gives equivalent early EFS to patients treated with allogeneic related or alternative donor BMT. Longer observation will be required to see if this results in a difference in long term EFS. The COG AALL0031 protocol (open 2002 - 2006) gave imatinib at 340 mg/m2 for an increasing number of days in combination with an intensive chemotherapy backbone. If an HLA-identical sibling donor was available, a BMT was performed after the first two cycles of therapy post induction otherwise chemotherapy was continued. BMT patients received imatinib starting 4 - 6 months post BMT for a 6-month duration. Ninety-three patients were treated, 10 of whom had failed induction.

Kirk R. Schultz et al

Abstract #4 - Blood, Volume 110, issue 11, November 16, 2007

[#735] Nilotinib Is Highly Active and Safe in Chronic Phase CML Patients with Imatinib-Resistance or Intolerance.

Nilotinib is an effective therapeutic option in CML-CP pts with imatinib-resistance or -intolerance, with an acceptable safety and tolerability profile. With longer follow up, cytogenetic response continues to increase and no change in safety profile has been observed on Nilotinib therapy.

Nilotinib is a novel, selective BCR-ABL inhibitor. It is more potent than imatinib against wild-type BCR-ABL and active against 32/33 imatinib-resistant BCR-ABL mutants. This analysis includes data from 320 pts who received at least 6 months of Nilotinib therapy (70.6% imatinib-resistant; 29.4% imatinib-intolerant). The median age was 58 years, the median duration of CML was 57.3 months, and 50.3% were males. Treatment with Nilotinib is ongoing in 188 pts (58.8%) and 132 pts (41.3%) discontinued the treatment, 51 (15.9%) for disease progression, 51 (15.9%) for adverse events (AE). The median duration of Nilotinib exposure was 341 (1 624) days and the median average dose intensity was 792.1 mg/d (47.9 1111.6 mg/d). The dose was escalated to 600 mg BID in only 51 pts (15.9%).

Complete haematological remission (CHR) at baseline was reported in 114 pts. Of the remaining 206 pts, 157 (76.2%) achieved CHR in 1 month. MCyR was observed in 180 pts (56.3%): 128/320 pts (40.0%) had complete cytogenetic response (CCyR). The median time to CHR and to first MCyR was 1.0 and 2.8 months, respectively. The median duration of MCyR has not been reached. Minor and Minimal CyR was seen in 22 (6.9%) and 42 (13.1%) patients respectively. The most frequent Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia (27%), neutropenia (30%), anaemia (9%), and asymptomatic serum lipase elevation (15%).

Hagop M. Kantarjian, Andreas Hochhaus, Jorge Cortes, Giovanni Martinelli, Kapil N. Bhalla, Francis J. Giles et al

Abstract #735 - Blood, Volume 110, issue 11, November 16, 2007

[#1040] Nilotinib Is Associated with Minimal Cross Intolerance to Imatinib in Patients with Imatinib-Intolerant CML

Although Nilotinib and imatinib have some molecular similarities, minimal occurrence of cross-intolerance exists. These results also suggest important differences in safety profiles between imatinib and Nilotinib. Thrombocytopenia appears to be the only intolerant AE that may recur with Nilotinib. These results support Nilotinib s excellent tolerability and indicate that it can be used effectively in both CML-CP and -AP pts with imatinib-intolerance. Of 320 pts with CML-CP, 94 (29.4%) were enrolled for imatinib-intolerance for either non-hematologic and/or hematologic AEs, of these, 71 (76%) had Grade 3/4 AEs at study entry. Of 127 pts with CML-AP, 24 (18.9%) were enrolled for non-hematologic and/or hematologic imatinib-intolerance; of these, 16 (67%) had Grade 3/4 AEs at study entry. Some pts had >1 AE satisfying criteria for intolerance. Only 2/71 (3%) pts with non-hematologic imatinib-intolerance experienced a recurrence of similar Grade 3/4 AEs during Nilotinib therapy. Of 37 pts with hematologic intolerance to imatinib, 19/37 (51%) did not develop Grade 3/4 or similar events during Nilotinib therapy. Median duration of Nilotinib exposure was 350.5 days in CML-CP and 141.5 days in CML-AP with median dose intensities of 725.8 mg/d and 768.8 mg/d, respectively. Only 1 pt (CML-AP) required a dose escalation to 600 mg BID.

Jorge Cortes, Elias Jabbour, Andreas Hochhaus, Philipp le Coutre, Michele Baccarani, Kapil N. Bhalla et al

Abstract #1040 - Blood, Volume 110, issue 11, November 16, 2007

[#1029] Nilotinib Therapy after Dasatinib Failure in Patients with Imatinib-Resistant or -Intolerant CML in Chronic Phase (CP), Accelerated Phase (AP) or Blast Crisis.

Nilotinib has impressive clinical activity in patients that had failed on both on Imatinib and Dasatinib. In addition, Nilotinib tolerability and safety profile in this subset of pts was similar to that reported for pts who failed only Imatinib? Few therapeutic options are available for patients (pts) with CML who fail to benefit from or to tolerate first, imatinib, and then, a second generation TKI such as Dasatinib and Nilotinib. This phase II open-label study was designed to evaluate the safety and efficacy of Nilotinib in such pts who either failed or were intolerant to imatinib and Dasatinib. A total of 67 evaluable pts are reported with CML-CP (27), -AP (15), and -BC (25). A total of 22 (33%) pts with Dasatinib failure remained on Nilotinib and 45 (67%) discontinued (8 for adverse events, 27 for disease progression).

Francis J. Giles, Phillip le Coutre, Kapil N. Bhalla, Gert Ossenkoppele, Giuliana Alimena, Ariful Haque etc

[#2963] Skin Changes on Continued Imatinib Therapy in Patients with Ph+ CML

IM causes dose-independent hypo- or hyperpigmentation of the skin in a significant number of Indian patients with Ph+ CML. This apparently happens due to modified melanin metabolism through the tyrosine pathway. Some of these changes (hyperpigmentation and extreme thinning) are bothersome from cosmetic viewpoint. The researchers reported the skin changes (generalized hypopigmentation) caused by imatinib mesylate (IM) in patients with Ph+ CML or GIST in earlier years already. Subsequent reports from MDACC confirmed such findings. Such changes could be different and more profound among the brown skinned people of India.

A cohort of 200 Ph+ CML patients at various phases of the disease receiving IM in a daily dose of 300 mg 800 mg (children 200 mg daily) were studied over a median period of 14 months (range 5 72 months). Skin changes of any kind or severity were noted in 120 (60%) patients. Hypopigmentation alone (usually generalized) was seen in 75 patients (32.5%), combined hypopigmentation and hyperpigmentation in 39 (19.5%), hypopigmentation + extreme thinning of the skin in 3 (1.5%) and the classical skin rash of grade 3/4 in 2 (1%). Skin changes occurred at all dose levels. Characteristically the hyperpigmented patches were localized to the facial area over the forehead and/or in a butterfly pattern across the malar areas and bridge of the nose. IM dose was not modified among patients with pigment changes alone.

Tapan Saikia et al, Mumbai, Maharashtra, India

[#1097] Reduced Intensity Stem Cell Transplantation and Donor Lymphocyte Infusion after Imatinib Induction To Eradicate Residual Disease in CML

Recommended first-line therapy for patients with chronic phase (CP) CML is imatinib mesylate (IM). Although IM induces complete cytogenetic responses (CCR) in the majority of patients, disease often remains detectable, likely reflecting stem cell persistence. Furthermore, primary and acquired resistance to IM have led to concerns about response durability. Allogeneic stem cell transplantation (SCT) remains the only curative option and with reduced intensity conditioning (RISCT) is less toxic and may be offered to a broader patient group.

The researchers novel approach used IM to establish disease control (CCR) in patients with newly diagnosed CP CML prior to RISCT (fludarabine/melphalan/MabCampath). Prophylactic escalating DLI was given for residual disease. 18 patients (4 centres) were recruited between 2001 and 2006. Dr. Holyoake from the UK presents data on 15 patients who achieved CCyR with IM and then had sibling mini-transplants using reduced intensity conditioning. 53% of patients had infection episodes and a few had GVHD. Follow-up was 31 months with 8 patients having sustained PCRU. 87% had to take DLI after transplant to induce PCRU. 50% of patients taking DLI had GVHD. 1 patient in the cohort died from transplant.

In this study, the patients receiving RISCT were in early CP with a CCR to IM. It is likely that the majority would have maintained CCR under Imatinib if not offered transplantation. However the number of patients who achieved undetectable Bcr-Abl following RISCT and DLI compares favourably with the response expected with IM alone. The patients have tolerated the transplant procedure well and are currently off all treatment for CML. Regular monitoring remains necessary, however if relapse occurs it should be DLI responsive. Currently IM is the accepted first line therapy in the majority of patients however we would highlight the importance of RISCT in selected groups and believe our approach is effective and well tolerated.

Tessa L. Holyoake et al, United Kingdom

Abstract #1097 - Blood, Volume 110, issue 11, November 16, 2007

[1036] Importance of Early Intervention with Dasatinib at Cytogenetic Rather Than Hematologic Resistance to Imatinib.

Recent data for patients with chronic-phase (CP) CML indicate that development of resistance or intolerance to imatinib and treatment intervention following progression to advanced-phase disease are both associated with poor clinical outcome. Results of a recent study confirm previous observations, emphasize the importance of close monitoring of treatment response to imatinib, and argue for early intervention in case of imatinib resistance. Late intervention, i.e. waiting for patients to lose a hematologic response, appears to significantly diminish the effectiveness of Dasatinib. Results demonstrate that intervention with a second-generation tyrosine kinase inhibitor is more effective for individuals with chronic-phase CML than for those with advanced-phase disease. Of note, development of hematologic resistance (loss of a complete hematologic response [CHR]) was identified as an independent prognostic factor with a 3-year survival rate of 57% (compared with 92% for patients who experienced cytogenetic resistance [loss of a major cytogenetic response (MCyR)]).

The objective of the current data analysis was to assess whether the development of hematologic resistance to imatinib would be a predictor of poor response to Dasatinib (SPRYCEL) relative to the development of cytogenetic resistance. Data from three Phase-II/III Dasatinib clinical studies (CA180-013 [70 mg BID], CA180-017 [70 mg BID], and CA180-034 [100mg QD, 50 mg BID, 140 mg QD, 70 mg BID]) in patients with CP CML with resistance to prior imatinib were evaluated. Consistent with our earlier findings, significantly higher complete cytogenetic response (CCyR) rates were reported for patients who had developed secondary or acquired cytogenetic resistance to prior imatinib than for those with hematologic resistance. The improved rates of CCyR in patients with cytogenetic resistance to imatinib were associated with prolongation of progression-free survival compared to patients with hematologic resistance, thereby confirming the importance of early intervention in the event of imatinib resistance and the significance of achieving CCyR with Dasatinib.

Hagop M. Kantarjian et al, MD Anderson Cancer Center, Houston, TX, USA

Abstract #1036 - Blood, Volume 110, issue 11, November 16, 2007

[1808] Vaccinations in CML Patients can improve response

We have previously shown that vaccination of chronic myelogenous leukaemia (CML) patients with CMLVAX100 (a mixture of 5 p210-b3a2 breakpoint derived peptides) plus GM-CSF was able to induce an evident and durable peptide-specific CD4+ T cell response in the majority of patients. In this pilot clinical trial the researchers showed that about 60% of 28 CML patients vaccinated while on imatinib, showed a reduction of their long lasting molecular residual disease after immunization (first 6 vaccinations) and about 25% of them achieved in addition a complete molecular response. The data suggest that the immune response induced in CML patients by CMLVAX100 vaccinations, consists of an increase of peptide-specific cytotoxic CD4+ T cells and a much more evident augmentation of CD4+/CD25+/FOXP3+ T cells that despite resembling a Treg phenotype display apparently no suppressive activity. The exact role of this peptide-specific CD4+ T cells subset in the context of CMLVAX100 mediated immune response needs to be further elucidated.

Monica Bocchia et al

Abstract #1808 - Blood, Volume 110, issue 11, November 16, 2007

[#2952] Comparison of Imatinib, Dasatinib, Nilotinib and INNO-406 in Imatinib-Resistant Cell Lines.

Second-generation ABL tyrosine kinase inhibitors (TKIs) such as Dasatinib, Nilotinib and INNO-406 (formerly NS-187) have been developed to override imatinib-resistance mechanisms. We directly compared the growth-inhibitory effects in imatinib-sensitive and resistant CML cell lines and the inhibitory profile for SRC family kinases (SFKs) among ABL TKIs. In conclusion, Dasatinib showed the strongest potency against BCR-ABL with less selectivity over SFKs. Nilotinib showed weaker affinity for SFKs compared to the other compounds, but was highly specific for ABL and may be useful for P-glycoprotein over expressing leukaemic cells. INNO-406 had intermediate affinity between Dasatinib and Nilotinib and inhibited LCK and LYN, in addition to ABL. Both Nilotinib and INNO-406 were potent inhibitors of the resistant-resistant T315A, F317L and F317V BCR-ABL mutations. These findings should be useful for treating imatinib-resistant patients with second-generation ABL TKIs.

Shinya Kimura, et al

[2940] Increased Cortical Bone Mineralization in Imatinib Treated Patients with CML.

It was recently suspected that hypophosphatemia develops in imatinib treated patients as a consequence of suppression of bone turnover and renal phosphate wasting. Recent data from 17 CML patients on imatinib therapy for a median of 50 months as well as 17 healthy volunteers shows that imatinib increases cortical bone mineral density and clearly rules out the previous concern of imatinib induced osteomalacia. It can be speculated that tyrosine kinase inhibitors could be novel antiosteolytic agents in skeletal disorders such as osteoporosis, myelomatosis and bone marrow metastatic diseases. Indeed, previous animal studies have shown that imatinib decreases osteoclastogenesis and osteoclast activity.

Sofia Jonsson et al, Gothenburg, Sweden

Abstract #2940 - Blood, Volume 110, issue 11, November 16, 2007

[2948] No further Evidence of Cardiotoxicity of Imatinib Therapy.

In the last year, the issue of cardiotoxicity of imatinib mesylate (IM) was on focus. Emerging data seem to deny an increased risk of cardiac events in patients treated with IM. B-type natriuretic peptide (BNP) is released by the heart in response to myocardial tension and is considered an accurate test for the diagnosis of heart failure. The measurement of BNP in the serum is a rapid and easy tool for evaluation of ventricular function, also in asymptomatic patients. We have measured BNP level in 50 consecutive patients (33 males and 17 females) with IM treated chronic phase CML. In conclusion, Imatinib therapy does not cause an increase in BNP levels. This gives an indirect confirm to the cardiac safety profile of the drug, as indicated also by the lack of major cardiac toxicities in our patients. BNP levels were affected by hypertension and by advanced age, but the latter could be a bias due to a higher incidence of hypertension in the elderly cohort.

Mario Tiribelli et al, Universitaria Udine, Italy

Abstract #2948 - Blood, Volume 110, issue 11, November 16, 2007

[1033] A Phase 3 Pilot Study of Continuous Imatinib Versus Pulsed Imatinib with or without G-CSF in Patients with Chronic Phase CML Who Have Achieved a Complete Cytogenetic Response to Imatinib

A randomised, multi-centre, pilot phase 3 study was established to determine the safety and efficacy of combining G-CSF with IM in patients with CP CML who had achieved CCR on IM. 45 patients were equally randomised between 3 arms: continuous IM (cIM); pulsed IM (pIM 3 weeks IM and 1 week no drug); and pIM-G-CSF (pIM-G 3 weeks IM and 1 week G-CSF). The dose of IM administered was the dose on which the patient had achieved CCR. In conclusion both experimental arms appeared safe and well tolerated. In this pilot study there was no clear difference in efficacy when either pIM or pIM-G was compared to cIM, despite the 25% effective dose reduction of IM in the experimental arms. The absence of a clear benefit means that this approach cannot be recommended as an alternative to standard IM dosing, however may be applicable to a selected group of patients who cannot tolerate standard daily dosing.

Nicholas Heaney, Mark Drummond, Jaspal Kaeda, Franck Nicolini, Richard Clark, George Wilson, Pat Shepherd, Jane Tighe, Lorna McLintock, Timothy Hughes, Tessa L. Holyoake

[734] Efficacy of Dasatinib in Patients with Chronic-Phase Chronic Myelogenous Leukemia with Resistance or Intolerance to Imatinib: 2- Year Follow-Up Data from START-C (CA180-013)

Dasatinib (SPRYCEL) is 325-fold more potent than imatinib against BCR-ABL in vitro and binds to BCR-ABL in both the inactive and active, oncogenic conformations. Dasatinib has been shown to be an effective treatment option for patients with imatinib-resistant or - intolerant chronic-phase chronic myelogenous Leukemia (CP-CML). Here we report the extended follow-up of START-C, a 75-center, international study of resistant in 387 patients with CP-CML with resistance (n=288) or intolerance (n=99) to imatinib.

Recruitment took place from February to July 2005. Dasatinib was administered on a 70-mg BID regimen; dose escalation (90 mg BID) or reduction (50 or 40 mg BID) was allowed for lack of response or toxicity, respectively. Median time from diagnosis of CML was 61 months (range 32- 50). Prior therapy included interferon- in 65% of patients and stem- cell transplantation in 10%; 55% had received prior imatinib doses >600 mg and 53% treatment with imatinib for >3 years. Best response to prior imatinib therapy was complete hematologic response (CHR) in 82%, and complete (CCyR) and partial cytogenetic response (PCyR) in 19% and 18%, respectively. With a median follow-up of 15.2 mo, CHR was attained in 91% of patients (95% CI 87-93%), major cytogenetic response (MCyR) in 59% (95% CI 54-64%) (52% imatinib-resistant, 80% imatinib-intolerant), and CCyR in 49% (40% imatinib-resistant; 75% imatinib-intolerant).

For patients with no prior MCyR to imatinib, 42% achieved a MCyR with resistant. A MCyR rate of 59% was recorded for patients with baseline BCR-ABL mutations; responses were seen across all mutations with the exception of T315I. MCyRs were durable, with only 7 of the 230 patients who had achieved a MCyR with resistant losing this response. Major molecular response rate (i.e., a BCR-ABL/ABL ratio of <0.1% according to the international scale by RQ-PCR) at 12 months was 25%. Progression-free survival at 15 months was 90% while overall survival was 96%. Dose interruptions were required for 87% of patients and dose reduction for 73%; the average daily dose administered was 101 mg (range 11-171). Reports of grade 3-4 thrombocytopenia and neutropenia were documented for 48% and 49% of patients, respectively. Non-hematologic toxicity consisted primarily of diarrhoea (37%), headache (32%), fatigue (31%), and dyspnoea (30%). Pleural effusion was experienced by 27% of patients; this was categorised as grade 1-2 in 21% and grade 3-4 in 6%. Dasatinib-induced cytogenetic responses remain durable in patients with CP-CML resistant or intolerant to imatinib.

Richard M. Stone, Hagop M. Kantarjian, Michele Baccarani, Jeffrey H. Lipton, Timothy Hughes, Rana Ezzeddine, Eric Bleickardt, Andreas Hochhaus

Abstract #734 - Blood, Volume 110, issue 11, November 16, 2007