Cycles Of Induction Therapy Research Articles

Baseline subclinical sensory deficits and the development of pain and numbness in patients with multiple myeloma (MM) being treated with chemotherapy.

9082 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity experienced by patients with MM. Patients may develop painful and non-painful (e.g., numbness) symptoms that impair function and often persist after therapy is terminated. This study examined the predictive value of baseline subclinical sensory deficits on the development of treatment-related pain and numbness. Methods: Patients (N=56) who had two or fewer cycles of induction therapy and no obvious neuropathy were assessed for sensory deficits using quantitative sensory testing (QST). Patients reported the severity of pain and numbness (on a 0-10 scale) at least weekly via the MD Anderson Symptom Inventory during induction (up to 16 weeks); 15 of 56 patients provided data for up to 16 additional weeks of maintenance therapy. These values correlate to patient reported pain and numbness in the hands/feet. Based on data collected from healthy controls, patients were classified as being with or without a sensory deficit at baseline on each QST domain. We fit linear mixed models for pain and numbness with each sensory deficit and time, controlling for cumulative cycles, diabetes, age, and treatment agent. Data is shown as mean ± standard deviation. Results: Patients who showed baseline deficits in sharpness detection (20%) reported significantly lower levels of pain (1.2±1.9 vs 3.1±2.9, p=.004) and numbness (0.4±0.8 vs 2.4±2.6, p<.001) during induction therapy and less numbness (0.0 vs 3.5±2.8, p=.001) during maintenance therapy. Further, those who showed deficits in warmth detection (40%) reported higher levels of pain (5.2±2.8 vs 1.7±2.3, p<.001) and numbness (5.8±2.2 vs 1.6±1.8, p<.001) during maintenance therapy. Finally, those with lower skin temperature (47%) reported higher levels of pain (4.5±2.3 vs 1.7±2.9, p=.005) during maintenance therapy. Conclusions: Our results suggest that subclinical sensory deficits may be useful in determining a patient’s risk for developing CIPN prior to initiation of induction therapy. This information could be used to provide patients with more-personalized chemotherapy plans that take into account their neuropathy risk.

The Prognostic Value of FDG PET/CT Prior to Autologous Stem Cell Transplant in Mantle Cell Lymphoma

Abstract 3113 Background:Pre-transplantation FDG-PET/CT (PET/CT) has been associated with progression-free survival (PFS) and overall survival (OS) in patients (pts) with relapsed Hodgkin's and diffuse large B-cell lymphoma (Spaepan, Blood.102 :53-59, 2003). However, no data exist regarding the role of PET/CT pre-transplant in pts with mantle cell lymphoma (MCL). We performed a retrospective analysis of pts with MCL and available pre-transplant PET/CT to evaluate the association of pre-transplant PET/CT findings with PFS and OS. Methods:PET/CT was reviewed by a single radiologist according to International Harmonization Committee (IHC) criteria with mediastinal blood pool as the referenced background activity and also utilizing liver blood pool. Bone marrow (BM) uptake was not utilized in the PET/CT response assessment. Associations between PET/CT positivity and clinical characteristics were performed using Fisher's Exact and Wilcoxon rank sum tests. PFS curves were constructed from date of transplant until date of relapse or death by the Kaplan-Meier method and evaluated by the log-rank test. Univariable proportional hazards models described the relationship between clinical variables and PFS. Results:Twenty-nine pts with PET/CT prior to autologous stem cell transplant were included. Median age was 60 (range 37–73), and 86% were male. Median MIPI was 5.9 (range 4.9–7.0), with 36%, 40%, and 24% of pts classified as low (< 5.7), intermediate (5.7–6.2), or high risk (> 6.2), respectively. At diagnosis, 93% of pts had BM involvement, 56% had splenomegaly, and 27% had bulky adenopathy ≥ 5cm. Sixty-nine percent of pts were induced with RCHOP and methotrexate (RCHOP+M, Damon, JCO 27 :6101–6108); other therapies included RCHOP (n=4), RHyperCVAD (n=2), bortezomib (n=2), and REPOCH (n=1). Sixty-six percent, 21%, and 14% of pts received 2, 3–5, or 6 induction cycles prior to transplant, respectively. Conditioning regimens were BEAM (59%) and BEC (41%) and 90% of pts underwent transplant in first remission. Median time to transplant from diagnosis was 5.4 months (range 3.4–82). With a median follow up of 18 months (range 0.7–43), estimated median PFS is 42 months (95% CI 15–45). There have been 7 relapses (4 RCHOP, 1 RCHOP+M, 1 bortezomib, 1 REPOCH) and 5 deaths (disease progression, n=3, and pneumonia, n=2). Seventeen pts (59%) had a negative PET/CT prior to transplant, with identical results using mediastinal or liver blood pool. In 19, 6, and 4 pts respectively receiving 2, 3–5, and 6 cycles of induction therapy, 58%, 50%, and 75% were PET/CT negative prior to transplant. PET/CT positive pts received RCHOP+M (n=10), RCHOP (n=1), and bortezomib (n=1), Compared to PET/CT negative pts, PET/CT positive pts were younger (median age 55 v. 62, p=0.04) with lower MIPI (p=0.05). There was no significant association of bulky adenopathy (p=0.09), induction with RCHOP+M (p=0.23), or number of induction cycles (p=0.87) with PET/CT findings. 5 pts had a positive pre-transplant BM biopsy, of which 2 were BM negative by PET/CT. BM positivity on pre-transplant PET/CT was observed in 14 pts with only 3 also positive by BM biopsy. Median PFS was 45 months (95% CI 13–45) for PET/CT negative pts and 33 months (95% CI 3–33) in PET/CT positive pts (Figure 1; p=0.03). At this time, 4 of 17 PET/CT negative pts have progressed or died compared to 5 of 12 PET/CT positive pts. Of the 5 deaths experienced thus far, 4 have occurred in PET/CT positive pts. Presence of bulky adenopathy ≥ 5cm was also associated with a worse PFS (p=0.01), but MIPI (p=0.31) and age (p=0.61) were not. Conclusions:PET/CT associates with PFS after autologous stem cell transplantation in MCL (p=0.03). However, additional follow-up is needed to see if this association between PET/CT positivity and early relapse in MCL persists. In addition, as the majority of pts had 2 cycles of induction therapy with RCHOP+M, the impact of treatment regimen and number of cycles is difficult to assess in this series. Interestingly, neither age nor MIPI were associated with PFS from transplant, perhaps indicating that clinical characteristics at diagnosis are less important in pts that achieve a complete response by IHC criteria prior to transplant. Prospective investigation with centrally reviewed PET/CT scans compared with standard CT is required to determine the predictive role of pre-transplant PET/CT in MCL. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Next Generation Sequencing for Minimal Residual Disease Monitoring in AML Patients with FLT3-ITD,

Abstract 3548Minimal Residual Disease (MRD) monitoring has become an important tool for risk and treatment stratification in hematological malignancies. MRD monitoring in FLT3 mutated patients has been difficult in the past as FLT3-ITDs vary from patient to patient and individual primer/probe sets would be required to assess MRD over time. In the present study we evaluated next-generation sequencing (NGS) as a new tool for MRD monitoring in patients with FLT3-ITD and NPM1 mutations.Five pediatric and 5 adult AML patients with FLT3-ITD and 10 adult patients with NPM1 mutations were analyzed by NGS with a target coverage of 10,000 reads per amplicon. Pediatric samples were collected at diagnosis, day 22 and after consolidation chemotherapy while adult samples were collected at different time points (average 4 timepoints per patient). Samples were sequenced unidirectionally on eight-lane PicoTiterPlates on a GS FLX sequencing system. In total, 2,563,550 sequencing reads were generated, corresponding to a total of 1,176,171 high-quality sequencing reads. NPM1 mutations were analyzed by quantitative RT-PCR using the MutaQuant kit from Ipsogen (Ispogen, Marseille, France). Allelic ratios of FLT3-ITDs were determined by fragment analysis on a DNA sequencer using GeneMapper software 4.0.First, the sensitivity of NGS to detect mutated alleles was evaluated by sequencing serial dilutions of a patient sample that had 46.3 percent mutated FLT3-ITD alleles at diagnosis. With a target coverage of 10,000 sequences and an allelic ratio of 46.3 percent the theoretical detection sensitivity was at most 1 in 4630 sequences. In fact, the allelic ratio in the sequenced samples linearly decreased in the tested dilutions down to the 5×10-4 dilution (Pearson correlation R2=.996). Samples from healthy volunteers were tested negative for both FLT3-ITD and NPM1 mutations (n=3). Allelic ratios from three diagnostic specimens of FLT3-ITD mutated patients were highly reproducible when determined in two independent NGS runs.As proof of principle we analyzed NPM1 mutated patients by NGS and quantitative RT-PCR in parallel. The mean allelic ratio of NPM1 mutants at diagnosis was 0.37 (range 0.29–0.46). An allelic ratio of 0.37 and 0.4 was measured in peripheral blood of two patients, and thus was similar to ratios in bone marrow. Concordant results between NGS and qRT-PCR were found in 38 samples (95%), whereas in two samples one method did not detect the mutation while the other did (NGS and RT-PCR were negative once each). We analyzed relapse samples in four patients. The NPM1 mutation was detected consistently by both methods in three patients at allelic ratios of 0.013, 0.19, and 0.32, while one patient had lost the mutation at relapse. One patient had an atypical NPM1 mutation for which no RT-PCR kit was available. NGS allowed quantification of the allelic ratio in this patient, which was 0.37 at diagnosis, 0.06 after one cycle of induction therapy, and 0 after the second cycle of induction therapy.In FLT3-ITD mutated patients we could determine insertion site, insertion length, number of individual clones, and allelic ratio from NGS data. The mean allelic ratio in diagnostic samples was 0.27 as measured by NGS and 0.4 as measured by fragment analysis. Three follow up samples were negative by fragment analysis, while a small clone could still be detected with NGS in these samples (allelic ratio 0.0004 to 0.001). All other samples were concordant between fragment analysis and NGS.NGS was used to determine MRD status in 5 patients with childhood AML harboring mutated FLT3. A reduction of 2–3 orders of magnitude was achieved during induction chemotherapy. During consolidation a further decrease or disappearance of mutated alleles was achieved in 3 patients, who remained in remission. However, allelic burden increased in 2 patients after first consolidation treatment (HAM) by 9- and 735-fold compared to the allelic ratio after induction therapy, and they relapsed 74 and 303 days later. Thus, accurate determination of the FLT3-ITD allelic ratio by NGS may become useful to identify patients before overt relapse.In summary, we show that NGS can be used for minimal residual disease assessment in FLT3-ITD mutated AML patients. The sensitivity of the method is scalable depending on the read depth, however, an adequate sensitivity level for efficient MRD detection still needs to be determined. Disclosures:No relevant conflicts of interest to declare.

Final Report of a Phase II Trial of Vorinostat with Idarubicin and Cytarabine for Patients with Newly Diagnosed Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Abstract 763The combination of vorinostat, a panhistone deacetylase inhibitor with activity in relapsed AML (Blood 2008;111:1060), with idarubicin and ara-C has synergistic antileukemia activity in a sequence dependent fashion were optimal effect is observed when vorinostat precedes ara-C (Blood 2006;108:1174 and CCR 2009;15:1698). In a phase I trial, we documented the maximal tolerated dose of vorinostat to be 500 mg orally three times a day for 3 days with standard dose idarubicin (BJH 2010; 150:72). Based on this we performed a phase II trial of vorinostat with idarubicin and ara-C in front line AML and higher risk MDS. Patients ages 15 to 65 years with appropriate organ function and no core binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m2 IV daily × 3 (days 4 to 6), cytarabine 1.5 gm/m2 IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with 5 cycles of consolidation therapy with lower doses of the combination and up to 12 months of maintenance with single agent vorinostat. The study was designed to stop early if excess toxicity or low probability of event free survival (EFS) >28 weeks were likely. After a 3 patient run-in phase, 75 patients were treated. Median age was 52 (19–65) years, 29 (39%) were diploid and 11 (15%) were Flt-3 ITD. Therapy was well tolerated: no excess vorinostat related toxicity was observed. Induction mortality was 4%. Common toxicities included: diarrhea (72%), nausea and vomiting (65%), and skin toxicity (38%). No cardiac toxicity was observed. CR was documented in 57 (76%) patients and CRp in additional 7 (9%) for an overall response rate (ORR) of 85% (95% CI 0.75–0.91). No differences in response were observed in patients younger or older than 60 years. Seven (9%) patients received 2 cycles of induction therapy and 4 (44%) responded including 2 CR and 2 CRps. When analyzed based on molecular or cytogenetic features, 10 of the 11 patients with Flt-3 ITD achieved a CR and 1 a CRp (ORR 100%). All 6 NPM1 mut/Flt-3 wild type (WT) patients achieved CR. Presence of Ras mutations had no impact on response. Of the diploid patients, 25 (86%) achieved a CR and 2 a CRp (7%) (ORR 93%). Patients with other cytogenetic alteration excluding −5/–7 had an ORR of 93% including 23 (79%) CR and 4 CRp (14%). Only 9 (53%) patients with −5/−7 achieved a CR and 1 (6%) a CRp for an ORR of 64% (p=0.018). Responses were significantly higher than with standard IA therapy. With a median follow up of 82 weeks (5 to 132 weeks), the median OS for the whole group was 82 (range 3–134) and EFS 47 (3–134) weeks. Median OS and EFS for patients with Flt-3 ITD were 91 (range 6 to 134) and 66 (6–134) weeks. There was a trend towards better survival in the Flt-3 ITD patients versus the unmutated group (p=0.067). Patients with diploid cytogenetics had a median OS and EFS of 105 (5–134) and 68 weeks (5–134). There was a trend towards better survival in the diploid patients versus non-diploid patients (p=0.09). Survival was poorer in patients with −5/−7: OS was 34 weeks (range 3–92) and EFS 14 (3–92). Non-diploid non −5/−7 patients had a median OS of 92 weeks (5–119) and EFS was not reached (NR) (5–119). Nineteen patients (25%) were transplanted in CR#1. All patients had achieved CR/CRp before SCT. Eleven (57%) received an unrelated donor including 2 umbilical cords and two 1 antigen mismatch. Fifteen patients (79%) received ablative preparative regimens. Median OS and EFS had not been reached in the 19 patients transplanted. Robust induction of histone H3 acetylation was documented in 2 patients (2%). No induction of beclin was observed in any of the patients. Baseline levels of NRF2 were elevated in 6 of 34 patients (17%), CYBB 21 of 34 (61%), FOXO3 5 of 34 (14%), SOD1 11 of 34 (32%), SOD2 5 of 34 (14%), GST-PI 2 of 34% (6%), IL6 3 of 49 (6%), TIMP1 7 of 49 (14%), MMP9 4 of 49 (8%) and p38MAPK in 3 of 49 (6%). mRNA upregulation occurred in all genes starting as early as day 3 of therapy. Baseline levels of NRF2 and CYBB were associated with longer survival. No association between age or cytogenetics were found with NRF2 or CYBB. In summary, the combination of vorinostat with IA is associated with high induction response rates. Toxicity and EFS rules were not met and the study beat expectations. Further studies comparing it to standard IA or “7+3” programs and in patients with Flt-3 ITD should be proposed. Disclosures:No relevant conflicts of interest to declare.

Preliminary Evidences of Circulating Inflammatory Markers Associated with Symptom Development In Patients with Multiple Myeloma During Induction Therapy

AbstractAbstract 4734 Background:Disease progression in multiple myeloma (MM) is highly related to cytokines, particularly interleukin (IL)-6, which promotes the growth of MM and is essential for the proliferation of malignant plasma cells. However, there are few reports delineating the relationship between levels of circulating cytokines and the severity of symptoms that patients experience during induction therapy. Methods:Thirty-four patients with MM were enrolled in this ongoing study before or within 2 cycles of induction therapy (with majority of bortezomib based and few thalidomide based). Multiple symptoms were measured by M. D. Anderson Symptom Inventory – MM module (MDASI-MM) twice a week during induction therapy. Sera were collected at baseline and during every cycle of induction therapy to measure cytokines by Luminex Multiplex Bead Array assay. Using ordinal regression models, we examined the hypothesis that concentration of serum inflammatory cytokines would be associated with symptom burden in patients with MM during induction therapy, especially therapy induced symptoms. The modeling was adjusted for time from induction therapy, age, sex, staging, Eastern Cooperative Oncology Group performance status (PS), opioid use, and body mass index (BMI). Symptom severity ratings were treated as ordinal responses. A log scale of cytokine concentrations was used for modeling. Results:From longitudinal symptom profile modeling, in general, female patients and patients with poor PS (PS ≥ 2) reported significantly higher level of symptoms than male patients and those with good PS. Overall, the most severe symptoms included fatigue, muscle weakness, sleep disturbance, pain, drowsiness, numbness and bone aches during the induction period. Several sickness symptoms show a trend, although not statistically significant, of decrease during the first cycle of induction therapy. By the end of the first cycle of induction therapy, we observed significant increases in therapy induced symptoms which included numbness, muscle weakness, difficulty remembering, poor attention and diarrhea (all P<0.05). Thereafter, symptoms stabilized or increased in severity for the remainder of induction period (see figure 1 Lowess curves for selected symptoms items on MDASI). Among the panel of inflammatory cytokines and soluble cytokine receptors (sIL-6R and sTNF-R1), monocyte chemoattractant protein, and C-reactive proteindemonstrated statistically significant relationships with severity of the majority of symptoms over time of induction therapy. Because of the non linear trajectory of symptom development, we tested the relationship between symptoms and cytokines by therapy cycle. There were no statistically significant correlations between any symptoms and cytokines (IL-6, IL-8, IL-10, and interferon-gamma, IL-1 receptor antagonist, soluble receptors, and angiogenic factor, vascular endothelial growth factor. On the other hand, sIL-2R, IL-2, and TNF-a were significantly correlated with few symptoms. Conclusion:Soluble cytokine receptors can play an important role in the development of MM and treatment-related symptoms. Hierarchical dynamic modeling can be used to assess the statistical relationship between biomarkers and the severity of symptoms. With a larger sample, the symptom and cytokine profile by patient's tumor response will be analyzed to address the interaction between cytokines and disease as well as therapy-driven symptom burden. The results of these studies that yield empirical information on expected symptom burden could be very useful for the management of symptoms and improved clinical management of patients.Figure 1.Symptom severity profile during induction therapy in MM patients Disclosures:No relevant conflicts of interest to declare.

Comparing Toxicities and Survival Outcomes with Total Therapy 4 (TT4) for 70-Gene (R70)-Defined Low-Risk Multiple Myeloma (MM) to Results Obtained with Total Therapy 3 Protocols TT3A and TT3B

AbstractAbstract 368 Background:TT3, incorporating bortezomib and thalidomide with induction prior to and consolidation after melphalan 200mg/m2-based transplants and 3 year maintenance with VTD (year 1) and TD (years 2+3) in TT3A and with VRD for 3 years in TT3B resulted in a high CR rate of ∼60% and, in the 85% of patients with GEP-defined low-risk MM, 5-yr OS/EFS of 80%/78%; 5-year CR duration estimate was 88%. Patients and Methods:Phase III trial TT4 for low-risk MM randomized patients between standard (S) and light (L) arms. TT4-L applied 1 instead of 2 cycles of induction therapy with M-VTD-PACE prior to and 1 instead of 2 cycles of consolidation with dose-reduced VTD-PACE after tandem transplantation. M-VTD-PACE comprised melphalan, bortezomib, thalidomide, dexamethasone and 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide. TT4-S applied standard single dose melphalan 200mg/m2, while TT4-L used a 4-day fractionated schedule of melphalan 50mg/2 on days 1–4. VRD maintenance for 3 years was identical in both arms. Here we report, for both TT4 arms combined, on grade >2 mucosal toxicities, applying CTCAE version 3.0, and on efficacy (CR, EFS, OS) in relationship to TT3 in low-risk MM. At the time of analysis, median follow-up on TT4 is 10.7 months and on TT3A/B 62.3/33.4 months. To facilitate comparisons between trials with different follow-up times, TT3 data were backdated to follow-up time comparable to TT4 as of this reporting time. Results:Baseline characteristics were similar in TT3 (n=364) and TT4 (n=165) in terms of B2M both >=3.5mg/L and >5.5mg/L, and elevated levels of CRP, creatinine, and LDH. Presence of cytogenetic abnormalities (CA) overall and in terms of CA13/hypodiploidy was similar in both. Fewer TT4 patients had ISS-1 (31% v 43%, P=0.010) and more had hemoglobin <10g/dL (35% v 26%, P=0.029). While neither trial had GEP-defined high-risk in the 70-gene model (R70), the more recently validated R80 distribution showed 7% high-risk in TT4 v 3% in TT3 (P=0.031). DelTP53 was more prevalent in TT4 than TT3 (39% v 10%, P<0.001), and MY favorable subgroup designation pertained to 3% in TT4 v 12% in TT3 (P=0.002). Toxicities are reported per protocol phase. During induction (TT4, n=160; TT3, n=364), grade >2 mucosal toxicities included colitis in 0%/1% (P=0.32), esophagitis/dysphagia in 0%/1% (P=0.33), GI mucositis, NOS in 1%/1% (P=0.99) and stomatitis/pharyngitis in 0%/1% (P=0.99). With transplant-1, (TT4, n=139; TT3, n=344), grade >2 mucosal toxicities included colitis in 3%/1% (P=0.24), esophagitis/dysphagia in 1%/5% (P=0.03), gastritis in 1%/0% (P=0.29), GI mucositis, NOS in 1%/2% (P=0.73) and stomatitis/pharyngitis in 0%/5% (P=0.008); with transplant-2 (TT4, n=105; TT3, n=294), grade >2 mucosal toxicities included colitis in 4%/3% (P=0.77), esophagitis/dysphagia in 0%/2% (P=0.20), GI mucositis, NOS in 2%/3% (P=0.99) and stomatitis/pharyngitis in 0%/1% (P=0.58). With consolidation (TT4, n=85; TT3, n=280), grade >2 mucosal toxicities included colitis in 0%/3% (P=0.36) and GI mucositis, NOS in 0%/1% (P=0.99). Timing of onset and final levels of CR differed substantially between TT4 and TT3 in favor of TT4 (P=0.006); no differences were observed in OS (P=0.36), EFS (P=0.66), and CR duration (P=0.12). Conclusion:TT4 (both arms combined) provided, despite higher proportions of patients with unfavorable characteristics than in TT3, superior CR rate and comparable survival outcomes to TT3's low-risk population. GI toxicities were reduced in TT4 v TT3. Results of TT4 arms will be presented.Patient characteristics:OverallProtocol %Factorn/N (%)TT4 (n=165)TT3 (n=364)P-valueAge >= 65 yr152/529 (29%)32270.341Albumin <3.5 g/dL179/528 (34%)4429<.001B2M >= 3.5 mg/L250/526 (48%)52460.216B2M > 5.5 mg/L109/526 (21%)25190.070Hb <10 g/dL152/528 (29%)35260.029LDH >= 190 U/L103/528 (20%)15220.052ISS Stage 1205/526 (39%)31430.010ISS Stage 2212/526 (40%)44390.292ISS Stage 3109/526 (21%)25190.070Cytogenetic abnormalities140/522 (27%)22290.080GEP 80-gene high-risk22/516 (4%)730.031TP53 deletion96/521 (18%)3910<.001 Disclosures:No relevant conflicts of interest to declare.

The role of maintenance pemetrexed in the treatment of non-small-cell lung cancer.

Until recently, the weight of evidence has supported the discontinuation of chemotherapy in advanced non-small-cell lung cancer (NSCLC) after 4-6 cycles of induction therapy. This allows patients with limited life expectancy a "treatment holiday." A minority of cases then go on to receive second-line therapy, although many deteriorate rapidly and never receive further active treatment. There has been renewed interest in the concept of maintenance from trials with pemetrexed and erlotinib. Both these agents can be given for long periods without serious cumulative toxicity in most patients. Both trials have shown significant extension of progression free survival in placebo-controlled trials. In cases who are not receiving pemetrexed as induction therapy, a statistically significant 5-month prolongation of overall survival in nonsquamous NSCLC has been reported. Treatment was well tolerated. This effect may reflect the early administration of an active second-line agent and it remains to be seen whether similar benefits will accrue to patients having pemetrexed as induction therapy.

Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

Thalidomide maintenance therapy after stem cell transplantation resulted in increased progression-free survival and overall survival in a few trials, but its role in non-transplant eligible patients with multiple myeloma remains unclear. This study assessed the impact of thalidomide-interferon in comparison to interferon maintenance therapy in elderly patients with multiple myeloma. Of 289 elderly patients with multiple myeloma who were randomized to thalidomide-dexamethasone or melphalan-prednisolone induction therapy, 137 finally completed 9 cycles of induction therapy with stable disease or better and thereby qualified for maintenance treatment. Of these, 128 have been randomized to either thalidomide-interferon or interferon alone. Primary study endpoints were progression-free survival and response rates; secondary endpoints were overall survival, toxicity and quality of life. Thalidomide-interferon maintenance therapy led to a significantly longer progression-free survival compared to interferon (27.7 vs. 13.2 months, P=0.0068), but overall survival was similar in both groups (52.6 vs. 51.4 months, P=0.81) and did not differ between patients aged 75 years or older, or younger patients (P=0.39). Survival after disease progression tended to be shorter in patients on thalidomide-interferon maintenance therapy (P=0.056). Progression-free survival and overall survival tended to be shorter in patients with adverse cytogenetic (FISH) findings compared to the standard risk group but differences were not significant (P=0.084 and P=0.082, respectively). Patients on thalidomide-interferon presented with more neuropathy (P=0.0015), constipation (P=0.0004), skin toxicity (P=0.0041) and elevated creatinine (P=0.026). Thalidomide plus interferon maintenance therapy increased progression-free survival but not overall survival and was associated with slightly more toxicity than maintenance with interferon alone. (ClinicalTrials.gov Identifier: NCT00205751).

Thalidomide-Interferon Vs. Interferon Maintenance Therapy After Thal-Dex Vs. MP Induction Therapy in Elderly Patients with Multiple Myeloma.

Abstract 2891Poster Board II-867Thalidomide maintenance therapy after completion of induction therapy plus ASCT and also after conventional therapy yielded conflicting results with some trials showing improvement in overall survival and others not.This study evaluates the efficacy of Thalidomide plus Interferon a2b (Thal-IFN) in comparison to interferon a2b (IFN) as maintenance therapy in elderly pts with multiple myeloma. For induction therapy, 289 pts had been randomized to either Thalidomide-Dexamethasone or to Melphalan-Prednisolone; results of this part of the study had been reported previously (BLOOD, 113, 3435-3442, 2009). 137 pts who had completed 9 cycles of induction therapy and had achieved stable disease or better were eligible for maintenance treatment, and 128 (median age 72 years, range 54 - 86 years) had finally been randomized to either Thal (starting dose: 200mg/day) in combination with IFN-a2b (Schering-Plough, 3 Mega U, TIW) or IFN a2b (IFN) at the same dose/schedule only. All pts were scheduled for zoledronate 4mg, q 4 weeks. Median follow up from randomization to maintenance: 35 mos. Median duration of maintenance therapy: 13.2 mos and 8.3 mos for pts randomized to Thal-IFN or to IFN, respectively (logrank test p=0.20).Maintenance therapy with Thal-IFN resulted in an improvement in the depth of response from PR to VGPR or CR in 5 (8%) and with IFN in 2 (3%) pts, respectively. Progression-free survival (PFS) was significantly longer in the Thal-IFN (27.7 mos) compared to the IFN only maintenance group (13.2 mos), (HR, 0.55; 95% 95% CI, 0.36-0.86; log-rank test, p=0.0068). Analysis of PFS by either Thal-Dex or MP induction therapy showed a significantly shorter PFS in pts started on Thal-Dex and subsequently randomized to IFN maintenance only (7.8 mos, log-rank test, p=0.037). PFS was 27.7 mos in pts started on Thal-Dex followed by Thal-IFN, 20.2 mos in those with MP induction therapy followed by IFN, and 27.6 mos in pts with Thal-IFN maintenance after MP induction therapy.Overall survival (OS) was similar in both groups (Thal-IFN 52.6 mos and IFN 51.4 mos, HR: 0.93, 95% CI: 0.53-1.66, log-rank test; p=0.81). OS by induction therapy did not vary significantly between the four treatment groups (logrank test, p=0.99). No significant difference in OS was seen between pts younger than 75 years and those aged 75 years or older (logrank test, p=0.39).Survival after progression of disease tended to be longer in pts who received IFN maintenance therapy only compared to those started on Thal-IFN (HR: 1.75, 95% CI, 0.97 – 3.14, logrank test: 0.056), while OS was similar between both groups when analyzed from termination of maintenance therapy (HR: 1.20, 95% CI, 0.65 – 2.20, log rang test 0.57).Baseline scores of the EORTC QLQ C30 items general health (Thal-IFN, mean 56; IFN, mean 59) and overall quality of life (Thal-IFN, mean 58; IFN, mean 60) were markedly below the score obtained in an healthy population (mean 75.3 and 73.3 respectively), but did neither differ at baseline between both groups nor did they vary significantly during the course of the maintenance (statistics will be provided). Cytogenetic data were available in 66 pts. PFS tended to be longer in pts with adverse FISH findings [t (4; 14), t (14; 20) Del 17p and abnormalities of 1q21] compared to the standard risk group, but differences were not significant (median: 31.5 vs. 21.6 mos, HR: 1.69, 95% CI, 0.13 – 3.07, log-rank test 0.084). The median of OS was 72.3 mos in those with standard risk and 39.6 mos in those with high risk features (HR: 1.94, 95% CI 0.91-4.13, log rank test: 0.082).In multivariate analysis (Cox model) only Thal-IFN maintenance therapy was shown to correlate significantly with PFS (HR: 0.61, 95% CI: 0.39-0.89, p=0.04) while for poor performance status, low hemoglobin, and low albumin a statistically non-significant correlation with survival was noted.Hematologic toxicity was similar between both groups. Pts on Thal-IFN maintenance experienced significantly more neuropathy (p=0.0024), constipation (p=0.0007) and skin toxicity (p=0.0063) and increase in renal impairment (p=0.037). In addition, there was a tendency for more dyspnea (p=0.40) and more fatigue (p=0.11) in pts on Thal-IFN maintenance therapy. Other non-hematological toxicities were similarly distributed in both therapy arms.In conclusion, Thal-IFN maintenance therapy resulted in increased PFS compared IFN maintenance treatment only, but OS was similar between both groups. Disclosures:Ludwig:Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria. Hajek:Janssen-Cilag: Honoraria. Kuhn:Schering-Plough: Employment.

Prevalence and Prognostic Impact of CEBPA mutations in Children with AML Treated with the AIEOP-LAM 2002/01 Protocol.

Abstract 2643Poster Board II-619C/EBP is a transcription factor that regulates terminal granulocytic differentiation. CEBPA mutations have been associated with improved outcome in both adult and pediatric patients with acute myeloid leukemia (AML). However, the impact in different treatment protocols, as well as the different outcome between single and double mutants, is still to be definitively established. We evaluated the prevalence and prognostic significance of CEBPA mutations in children with de novo non promyelocitic AML treated in Italy with the AIEOP-LAM 2002/01 pediatric protocol. Among 205 patients enrolled in the protocol between December 2002 and December 2007, 103 were successfully analyzed for CEBPA mutations by PCR amplification of TAD and bZIP domains of the gene, and through sequencing of positive cases after DHPLC analysis. Characteristics of analyzed and non analyzed patients were not statistically different. Two types of CEBPA mutations, N-terminal (TAD) truncating mutations and in-frame bZip domain mutations, were detected in 13/103 (12.6%) patients tested; 8 of them (61.5%) harboured both mutation types.Laboratory, clinical characteristics and outcomes for patients with CEBPA mutations were compared to those of patients with wild-type CEBPA. CEBPA mutations were significantly more common in older patients (8/13 vs 30/90 children were older than 10 years), in patients with FAB M1 (7/13 vs 4/90), and in patients with normal cytogenetics (13/13). None of the CEBPA mutated cases carried either FLT3 or NPM1 mutations. Only 1 mutated case was found in Standard Risk patients (defined as children carrying isolated CBF abnormality and achieving complete remission after 1 cycle of induction therapy), while the other 12 patients belonged to the High Risk group.Although the values did not reach statistical significance because of the low prevalence of CEBPA mutations, with a median follow up of 39 months (range 4–86) the event-free survival probability at 5 years was 76.9% vs. 59.6% for children with or without CEBPA mutations, respectively. The values for Disease-Free Survival were 83.3% vs. 65.4% and those for Overall Survival were 90.0%. 66.4%, respectively. No difference in terms of outcome was found between patient with a single and those with double mutants, neither between those with TAD- and bZIP- mutations.Therefore, patients in the AIEOP-LAM 2002/01 pediatric trial carrying CEBPA mutations seem to have a lower relapse rate and improved outcome, their overall survival approaching that of children belonging to the Standard Risk group (90% vs. 97%). If confirmed in a larger cohort of patients and with longer follow-up, these data suggest that CEBPA mutation analysis could be usefully employed to identify patients at lower risk of treatment failure and for allocating them into different classes of risk. Disclosures:No relevant conflicts of interest to declare.

Risk Stratification and Prognostic Factors in Elderly AML Patients – Updated Results of 909 Patients Entered Into the Prospective AML96 Trial.

Abstract 329▪▪This icon denotes an abstract that is clinically relevant. Background:Acute Myeloid Leukemia (AML) is a life threatening disease requiring intensive induction treatment for long-term survival. Since the majority of patients are older than 60 years at diagnosis, balancing pros and cons of intensive chemotherapy is difficult. In this context prognostic factors are important tools for clinical judgement, decision making and patient information. We present here our analysis of potential prognostic factors derived from the updated data of a large multicenter trial for patients with AML older than 60 years, who were treated according to the same protocol. Patients and Methods:The prospective AML96 trial of the Study Alliance Leukemia (former DSIL) included 909 patients with a median age of 67 years (range, 61-87). Protocol treatment included two cycles of induction therapy containing daunorubicin and cytarabine in a 7+3 fashion (DA). Consolidation treatment consisted of m-amsacrine and intermediate dose cytarabine (10g/m2). Univariate and multivariate analyses using potential prognostic factors were performed for the following outcomes: complete remission (CR), overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) / time to progression (TTP). Results:The median follow-up time is 68 months (5.66 years). Of all treated patients, 414 (45%) completed two cycles of DA induction according to the protocol, 181 (20%) received only one DA, and 111 patients (12%) died during the first induction cycle. The remaining 203 patients (23%) received a second induction cycle outside the protocol due to insufficient response to the first induction. 203 patients received a consolidation treatment after two cycles of induction. 454 of all 909 patients reached a CR (50%). The independent prognostic factors for achieving CR were karyotype, NPM mutation status, white blood cell count (WBC), blast count at day 15 after initiation of first induction, CD34 expression and secondary versus primary AML. The median OS, DFS and TTP were 0.76, 0.76 and 0.88 years, respectively. Five-year OS, DFS and CIR were 9.7%, 14% and 79.1% respectively. Multivariate analyses revealed that karyotype, NPM mutation status, white blood cell count (WBC) and LDH were of independent prognostic significance for OS, DFS and CIR. Even though NPM-FLT3 grouping showed a significant influence on all outcomes, it seems that in the age group above 60, the negative impact of FLT3 was less influential compared to the positive impact of NPM mutational status. Favourable and high cytogenetic risk groups displayed markedly different OS times irrespective of the other identified prognostic factors. However, the largest group of patients with intermediate-risk karyotype could be subdivided into two groups with distinct prognostic profiles: Based on hazard ratios from the Cox model, we established an additive risk model using the following relative points (in brackets): high CD34 expression (1 point), high WBC (1 point), higher age (2 points), high LDH (3 points), and mutated NPM (-2 points). Applying this model results in the following four groups: favourable cytogenetics, intermediate cytogenetics with favourable risk features (score ≤3), intermediate.cytogenetics with adverse risk features (score >3) and high risk cytogenetics. The 3-year OS of these groups were 39.5%, 30%, 10.6% and 3.3%, respectively. Conclusion:Results of a large cohort enable us to demonstrate that, depending on prognostic factors, elderly AML patients with an intermediate-risk cytogenetic profile can be subdivided into a more favourable group with an OS time span similar to CBF AML, and a group with a distinctively worse prognosis. The proposed risk-stratification score can serve as a tool for patient information and decision making with regard to treatment strategy. Whilst patients with CBF AML or with intermediate cytogenetics and favourable risk features potentially benefit from intensive induction treatment, patients with high-risk cytogenetics or intermediate risk with adverse prognostic features have very poor OS rates despite intensive chemotherapy. From our study we conclude that this group of patients could be spared the potential side effects of intensive induction and should instead be offered best supportive care or alternative treatment approaches. Disclosures:No relevant conflicts of interest to declare.

Incorporation of Thalidomide-Dexamethasone (Thal-Dex) into up-Front Double Autologous Stem-Cell Transplantation (ASCT) for multiple Myeloma: Final analysis of phase II “Bologna 2002” Study.

Abstract 349▪▪This icon denotes an abstract that is clinically relevant.We report here on the final analysis of the multicenter phase II “Bologna 2002” study which incorporated thal-dex into double ASCT with high-dose melphalan (200 mg/m2) as front-line therapy for younger patients with symptomatic multiple myeloma (MM). By study design, thal (200 mg/day) and pulsed low-dose dex (160 mg/month, with two added 4-day courses on the first and third cycle of induction therapy) were administered from the outset until the second ASCT. The analysis was performed on an intention-to-treat basis on a total of 357 patients who were followed for a median of 43 months. Their median age was 57 years, 86% had advanced disease stage. More than 80% of the patients were screened at diagnosis for the presence of cytogenetic abnormalities (FISH) on CD138+ bone marrow plasma cells, including del(13q) (45%), t(4;14) (14%) and del(17p) (6%). The rate of at least VGPR increased from 31% after thal-dex induction therapy to 60% after the second ASCT. The final CR rate was 33% for all the patients and 44% for those who actually received pre planned double ASCT. Median TTP and PFS were 68 and 47 months, respectively, with 5-year projected rates of 45% and 33%. The 5-year projected OS rate was 65%. TRM after the first and second ASCT was 0.5% and 2%, respectively. Median OS after relapse or progression was 30 months, suggesting that short-term thal exposure had no adverse influence on response to salvage therapies. The quality of response following ASCT(s) influenced clinical outcomes. In particular, patients achieving CR had significantly longer PFS and OS than patients in VGPR (PFS: median 68 vs 48 months, respectively, P=0.04; 5-year projected OS 84% vs 72%, respectively, P=0.02). Similarly, patients in VGPR had better outcomes compared with patients achieving PR (P=0.02 and 0.04 for PFS and OS comparisons, respectively). In a multivariate analysis, best response (at least VGPR) ever achieved and low beta2-m were the most important variables significantly extending TTP (P=0.04), PFS (P=0.000) and OS (P=0.003). Additional variables predicting for prolonged PFS were the absence of del(13q) (P=0.002) and del(17p) with or without t(4;14)(P=0.03). OS was favourably influenced also by IgG isotype (P=0.04) and absence of high-risk cytogenetic abnormalities [del (17p) +/- t(4;14)(P=0.03)]. A case match comparison of 135 patients enrolled in “Bologna 2002” study with an equal number of pair mates included in the previous “Bologna 96” study of double ASCT without thal confirmed the benefits from the addition of thal-dex to double autotransplantation in terms of rate (P=0.001) and duration (p<0.001) of at least VGPR, TTP (P<0.001) and PFS (P=0.001). In conclusion, attainment of CR and VGPR was a major determinant of favorable outcomes for patients treated with thal-dex and double ASCT. Poor prognosis conferred by del(13q) and del (17p)+/- t(4;14) was not overcome by thalidomide, consistently with previous data reported in refractory MM patients and with thal as maintenance therapy after double ASCT. Short-term thal therapy, as applied in “Bologna 2002” study, was generally well tolerated, with limited toxicities leading to less than 10% discontinuation rate due to drug-related adverse events, and had no adverse impact on OS after relapse. Disclosures:Off Label Use: Thalidomide was incorporated into up-front treatment for patients with newly diagnosed multiple myeloma.

Treatment Rationale and Study Design for the PointBreak Study: A Randomized, Open-label Phase III Study of Pemetrexed/Carboplatin/Bevacizumab Followed by Maintenance Pemetrexed/Bevacizumab Versus Paclitaxel/Carboplatin/Bevacizumab Followed by Maintenance Bevacizumab in Patients with Stage IIIB or IV Nonsquamous Non–Small-Cell Lung Cancer

We present the treatment rationale and study design of the PointBreak study, a phase III study of pemetrexed/carboplatin/bevacizumab induction followed by pemetrexed/bevacizumab maintenance (arm A) compared with paclitaxel/carboplatin/bevacizumab induction followed by bevacizumab maintenance (arm B) in patients with advanced nonsquamous Non–Small-cell lung cancer (NSCLC). Treatment consists of up to 4 cycles of induction therapy followed by maintenance therapy until disease progression or treatment discontinuation in approximately 900 patients (450 per treatment arm). The efficacy objectives of this study are to compare overall survival (OS), response rates, disease control rates, progression-free survival, and time to progressive disease between the 2 treatment arms. In addition, safety, quality of life, pharmacokinetics, and translational research will be investigated for both treatment arms. If the primary objective (OS) is achieved, this study will provide robust results on an alternative treatment option, pemetrexed/carboplatin/bevacizumab followed by maintenance therapy with pemetrexed/bevacizumab, for patients with nonsquamous NSCLC.

A Phase III Study of Enoxaparin Versus Low-Dose Warfarin Versus Aspirin as Thromboprophylaxis for Patients with Newly Diagnosed Multiple Myeloma Treated up-Front with Thalidomide-Containing Regimens

Thalidomide-containing regimens are currently being used as standard initial therapy for both younger and elderly pts with multiple myeloma (MM), but are associated with an increased risk of venous thromboembolism (VTE) which necessitates routine thromboprophylaxis. Controversies exist concerning the best thromboprophylactic regimen to be used in these pts. To address this issue, the Italian Myeloma Network GIMEMA designed a phase III sub-study aimed at prospectively investigating the efficacy and safety of low molecular weight heparin (LMWH) or fixed low-dose warfarin (WAR) or low-dose aspirin (ASA) as prophylaxis against VTE in newly diagnosed MM pts who were randomized to receive primary induction therapy with thalidomide-containing regimens in the context of 2 phase III studies conducted by the same group. In one of these studies, pts with ≤65 years of age were randomly assigned to receive Velcade-Thalidomide-Dexamethasone (VTD) or Thalidomide-Dexamethasone (TD) before autologous transplantation. In the other study, Velcade-Melphalan-Prednisone (VMP) was compared with VMP plus thalidomide (VMPT) for elderly patients aged >65 years. The daily dose of Thalidomide was 200 mg in both VTD and TD, and 50 mg in VMPT. Pts randomized to VTD or TD received a total Dexamethasone dose of 320 mg/cycle, while those assigned to VMP or VMPT were given a total Prednisone dose of 240 mg/m2/cycle. By sub-study design, pts treated on VTD or TD or VMPT were randomly assigned to receive thromboprophylaxis with LMWH (Enoxaparin, 40 mg/d) or WAR (1.25 mg/d) or ASA (100 mg/d) for the duration of induction therapy. At the opposite, pts randomized to VMP did not receive any prophylaxis and were used as controls. Sub-study end points included incidence of VTE, acute cardiovascular events, sudden death, bleeding and any other serious adverse events. At the time of the present analysis, 703 pts who received at least 3 cycles of induction therapy were evaluated. Of these pts, 164 treated on VMP were the control group, while the remaining 539 pts (of whom, 209 treated on VTD, 211 on TD and 119 on VMPT) were randomized to receive either LMWH (n=178) or WAR (n=180) or ASA (n=181). Baseline pts characteristics and risk factors for VTE were comparable in all sub-groups. Overall, the risk of VTE was 3.9% with WAR vs 4.5% with LMWH vs 5.5% with ASA (P values not significant for comparisons between different sub-groups), whereas it was 1.8% among the controls. Median times to onset of VTE for pts treated on LMWH or WAR or ASA were 2.66 vs 2.96 vs 2.10 months, respectively. Pts receiving Velcade-containing regimens (VTD or VMPT) had a VTE frequency in the range of approximately 3%, as compared to 5.8% for pts on TD (P value not significant). The rates of cardiovascular events were 0.6% in each of sub-groups including LMWH, WAR and controls, vs 1.1% for pts treated on ASA. No sudden deaths were reported. The incidence of all grades bleeding was 0.6% with LMWH vs 1.1% with WAR vs 3.3% with ASA (P values not significant for comparisons between different sub-groups), while it was 3.7% among the controls. In conclusion, results of the present analysis show that the overall risk of VTE among sub-groups of pts treated with different thalidomide-containing regimens was not superior to that expected during the natural course of MM. No significant relationship was found between the frequency of VTE and thromboprophylactic regimens, induction treatments (e.g. containing or not Velcade) and age of pts (e.g. young vs elderly). In comparison with LMWH and WAR, there was a higher, albeit marginal, risk of VTE and bleeding complications associated with ASA prophylaxis. Finally, a finding not previously well recognized, fixed low-dose WAR was not inferior to LMWH in reducing the risk of VTE among newly diagnosed MM pts receiving thalidomide-containing regimens. For these pts, LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens.

Timed Sequential Therapy Induction and Consolidation in Newly Diagnosed AML: Achievement of Leukemia-Free Survival in Patients Using Two Cycles of Therapy Alone

Long term outcomes for patients with AML are unsatisfactory following induction and consolidation chemotherapy alone except in patients with favorable–risk cytogenetics. The additional administration of the same or different agents starting 8–10 days after start of initial chemotherapy (timed sequential therapy, TST) may enable the killing of leukemic cells synchronized into cell cycling by the initial chemotherapy. However, it is unclear if patients with intermediate and unfavorable cytogenetics achieve improved outcomes using this approach. Sixty-nine unselected patients with AML (42M, 27F; median age = 53, range 16–74; cytogenetic risk group favorable =2, intermediate = 37, unfavorable = 23; 10 with an antecedent hematologic disorder) referred to a tertiary leukemia center received initial chemotherapy with a regimen of cytarabine 667mg/m2/d by 24 hour infusion on d1–3, idarubicin 12mg (age <60) or 8 mg (age >60)/m2/d on d1–3 and etoposide 100mg/m2 on d 8–10. Induction death occurred in 7 patients (10%). Complete remission was achieved following one cycle of induction therapy in 30 patients (43.5%). The corresponding complete response (CR) rates by cytogenetic subgroup were100%, 48.6% and 26% in the favorable, intermediate and unfavorable cytogenetic groups respectively. In patients who achieved CR, median time to ANC > 1000/mm3 and platelets > 100,000/mm3 were 29 d (range 21–76d) and 26d (range 17–83d). Mucositis was the most common non-hematologic toxicity. Of the 69 patients treated, 30 (43%) and 4 (6%) patients proceeded to allogeneic and autologous hematopoietic stem cell transplantation respectively. Of the patients who did not receive stem cell transplantation, eleven patients (median age 54, range 23–72; median WBC 27.1, range 1–250; cytogenetics -9 normal, 1 t(9;22); 1 11q23 abnormality) underwent consolidation with TST–consisting of a single cycle of cytarabine 667mg/m2/d (continuous infusion) on d1–3 and 10–12, and idarubicin (same dose as induction). Two year estimated probabilities of overall survival and relapse in this group were 65% and 26% respectively. In summary, TST as administered in these patients can be safe in patients with newly diagnosed AML, including those patients aged between 60 and 70. However, the regimen does not appear to improve CR rates over that seen using conventional induction regimens. Patients with intermediate risk cytogenetics who achieve CR and are not candidates for stem cell transplantation may receive consolidation with a single additional cycle of TST.

Prognostic Value of Bone Marrow Angiogenesis in Patients with Multiple Myeloma Undergoing High-Dose Therapy and Autologous Stem Cell Transplantation.

BACKGROUND. Angiogenesis is a constant hallmark of multiple myeloma (MM) progression. It has also been reported that bone marrow angiogenesis is a predictive factor of poor survival in newly diagnosed myeloma. The aim of the current study was to investigate the dynamics of bone marrow (BM) microvessel density (MVD) in patients undergoing high-dose therapy (HDT) and autologous stem cell transplantation (ASCT).PATIENTS AND METHODS. 36 patients with newly diagnosed MM (22 in stage II and 14 in stage III according to Salmon and Durie) were included in the study – 21 male and 15 female, median age – 51 ys (range 31–67). All patients underwent HDT that included 3–4 cycles of induction therapy (VAD), stem cell mobilization with cyclophosphamide 6 g/m2 and G-CSF 5 mcg/kg, EDAP and single or tandem ASCT with melphalan 200 mg/ m2. The BM biopsies for histological and immunohistochemical analysis were performed at the time of diagnosis, after induction, after stem cell mobilization before the 1st ASCT and after the end of therapy (5 times during the treatment). The Control group consisted of normal BM donors (7 male and 3 female, median age 29, (17–59)) who underwent BM biopsy during BM harvesting for alloBMT. Blood vessels were highlighted by immunostaining of endothelial cells with a monoclonal antibody to CD34 (Novocastra Lab Ltd). The MVD was calculated in 10 fields using an 40x objective and 16x ocular lens.RESULTS. At diagnosis in all MM pts, MVD was extremely high compared to normal donors (152±8 vs 74±4). A significant decrease of BM MVD was observed after each phase of therapy: after the induction therapy the MVD was 124±6; before the 1st ASCT – 109±5 and at the end of treatment – 97±3. There was a statistically significant increase of MVD after stem cell mobilization due to G-CSF (143±4). Although there was a marked decrease of BM MVD in MM pts with CR or VGPR, it nevertheless stayed significantly higher compared with control group (p<0,001). The analysis of probability of CR or VGPR duration after ASCT according to MVD at different phases of therapy showed that MVD at diagnosis and before the 1-st ASCT are important prognostic factors. Probability of duration of CR or VGPR was 63% in group with low MVD before the 1st ASCT compared with 15% in group with high MVD (p<0,02). MVD was revealed to be more powerful prognostic factor for progression free survival (PFS) then CR or VGPR achievement.CONCLUSION. BM angiogenesis is increased in patients with MM. BM MVD is decreased during and after treatment however even after the completion of HDT and ASCT, the MVD is higher then in the normal control group. There is a statistically significant increase of MVD after stem cell mobilization with cyclophosphamide and G-CSF. MVD at the time of diagnosis and before the 1-st ASCT are important prognostic factors for overall-survival and PFS after ASCT. MVD before the 1-st ASCT appears to be a more powerful prognostic factor for PFS then remission rate.

Preliminary Results of a Phase II Study of Low Dose Decitabine as a Single Agent in Older Patients (age≥60) with Previously Untreated Acute Myeloid Leukemia (AML)

The hypomethylating agent decitabine inhibits DNA methyltransferase (DNMT) enzymatic activity and is approved by the FDA for treatment of myelodysplastic syndromes. We previously performed a phase I trial in AML of decitabine (with or without the histone deacetylase inhibitor valproic acid); the trial was designed to establish a biologically effective dose (BED) of decitabine based on drug-induced re-expression of methylated and silenced genes. With the derived BED of 20mg/m2/day given for 10 days, every 4 weeks, clinical activity was observed in previously untreated older AML patients (pts, CR in 4/12); clinical response correlated with gene re-expression (Blum, JCO 2007). The addition of tolerable doses of valproic acid did not appear to improve clinical results or increase gene re-expression compared to decitabine alone. Therefore, we designed a phase II study of single agent decitabine for previously untreated AML pts of age≥60 who were not candidates for intensive chemotherapy (or who refused it). Performance status was ECOG <3. All pts received induction with decitabine at 20mg/m2 IV over 1 hour on days 1–10 of a 28 day cycle. The schedule for subsequent cycles was customized for each patient based on clinical response and/or toxicity (e.g., myelosuppression). Pts with persistent AML at the end of a cycle received a repeat of the 10 day treatment. In contrast, pts with <5% blasts received decitabine as consolidation for only 5 days/cycle (every 4 weeks for 1 year). For CR/CRi patients, the decitabine schedule could be reduced further to 4 or 3 days/cycle for Grade 4 neutropenia lasting more than 2 weeks, if applicable. 33 pts were enrolled; accrual was completed in 13 months. Pts had a median age of 74 years (range, 60–83); 24 pts were age≥70. 18 pts had de novo AML; 15 had secondary or t-AML. Pts had a median presenting white blood cell count of 2,400/uL (range, 400–58,800/uL) with median marrow blasts of 44% (range, 21–92%). 13 pts had complex karyotype (≥3 abnormalities); 12 had normal karyotype; one patient had t(8;21), and the rest had other abnormalities (with one unknown). This was a high risk group by any comorbidity measure. Scoring was as follows on four high-risk factors of age ≥70, antecedent hematologic disorder, unfavorable karyotype, and ECOG 2: 16 pts had 3+ risk factors; 15 had two, and the other 2 pts had one risk factor. Using the transplant comorbidity index for older AML pts (HCT-CI; Giles, BJH 2007), pts had scores of 3+ (N=18), 1–2 (N=10), or 0 (N=5). The median number of cycles received to date is 3 (range, 1–10); 17 pts continue to receive study therapy. 10 pts have received 4+ cycles. Of the first 22 consecutive pts enrolled, 11 achieved CR (50%); 4 more have achieved CRi by IWG criteria for response (Cheson, JCO 2003). 11 pts are <3 months since entry onto the study, with response evaluations ongoing. The response rate was similar between cytogenetic risk subgroups and in both de novo and secondary AML. 4 pts who achieved CR subsequently relapsed, with CR duration of 9, 6, 6, or 2 months, respectively. The other CR pts have maintained ongoing responses for 2–11+ months. 9/11 pts who achieved CR required only 1 cycle of induction therapy (10 day course) before initial response was achieved (CR, N=2; CRi, N=7). For pts who had CRi as initial response, the median number of additional cycles to achievement of full CR was 1 (range, 1–3). In this high risk group, death within 8 weeks of any cause occurred in 4 pts and was related to infection in each case. Though therapy was often administered in the outpatient clinic, febrile neutropenia and infections in the setting of drug and/or disease-related myelosuppression requiring hospitalization during the induction courses were frequent, occurring in nearly all pts. Post-CR therapy, however, was very well tolerated with no hospitalizations for complications during consolidation courses. In conclusion, decitabine in this novel schedule of induction with outcome-adapted modification of consolidation therapy was highly active and well tolerated by most in this poor risk cohort of older AML pts. Clinical results compare favorably to those seen in this population with low dose clofarabine (Erba, ASCO 2008a) or decitabine-5 day schedule (Cashen, ASH 2006a). Correlative studies including re-expression of epigenetically silenced genes, target gene promoter methylation, and global DNA methylation are ongoing.

Outcome of high-dose cytarabine-based induction therapy followed by hematopoietic stem cell transplantation in acute myeloid leukemia: influence of karyotype

One-hundred-twenty consecutive adult patients aged 15–69 years (median 40) with acute myeloid leukemia (AML) excluding t(15;17) received induction therapy comprising idarubicin, high-dose cytarabine and etoposide. Planned post-induction treatment included two courses of moderate-intensity consolidation therapy followed by stem cell transplantation. 11 patients (9%) died during induction therapy. The complete remission (CR) rate with a single cycle of induction therapy was 71%. The overall CR rate, after salvage chemotherapy but excluding allogeneic transplantation for primary refractory disease, was 82%. CR rates with one cycle of therapy for patients with good, intermediate and poor karyotype were 96, 72 and 41%, respectively (P < 0.0001). The impact of karyotype on the overall CR rate was also significant (96 vs. 88 vs. 59%; P = 0.001). Overall, 84 of 98 patients (86%) attaining CR underwent autologous (n = 59), allogeneic (n = 23) or syngeneic (n = 2) hematopoietic stem cell transplantation in first CR. The 5-year overall survival (OS) of 43% (95% CI: 34–52%) was significantly influenced by the karyotype: good 73%, intermediate 41%, and poor 18% (P = 0.0001). These data suggest that the sequence of therapy employed is active in AML, but additional steps are needed to improve the outcome of patients with intermediate- and high-risk cytogenetic abnormalities.

Early Reduction of Serum Free Light Chain Can Predict Therapeutic Responses in Multiple Myeloma.

Background M protein as measured by serum protein electrophoresis (SPE) is usually required for the diagnosis and therapeutic monitoring of multiple myeloma. However, SPE may not be able to detect M protein in some cases such as light-chain disease or non-secretory myeloma. Serum free light chain (FLC) assay has been recently developed and shown to be very helpful in such situations. Here, we evaluate the usefulness of this new test in the diagnosis and therapeutic monitoring of myeloma patients treated with bortezomib plus dexamethasone at our institution.Methods Serial serum FLC assays were performed before and after each cycle of induction therapy. All patients were treated with bortezomib plus dexamethasone every 3 weeks for four cycles. Treatment responses were determined according to the European Group for Blood and Marrow Transplantation criteria.Results There were total of 25 patients in this analysis. Fifteen were male (60%); the median age was 54 years (range, 35–68 years). Abnormal ratio of serum FLC was detected in 88% of pre-treatment serum samples. After four cycles of induction therapy, nine patients (36%) had achieved complete remission. No baseline clinical and laboratory parameters could correctly predict the therapeutic responses in these patients. When serial FLC assays were taken into account, we found that a more-than-40% reduction in the abnormal serum FLC after the first cycle of treatment was significantly associated with achieving complete response at the end of treatment (Pearson Chi-square, p = 0.041).Conclusions Serum FLC assay is very useful for the diagnosis of multiple myeloma and allows a more rapid assessment of therapeutic response. Further studies are needed to establish the role of this test in the era of highly effective anti-myeloma therapy.