Moderate Hematologic Toxicity Research Articles

CD20 CAR T cells safely and reversibly ablate B cell follicles in a non-human primate model of HIV persistence

CAR T-cell therapies have demonstrated immense clinical successes for B-cell and plasma-cell malignancies. We tested their impact on the viral reservoir in a macaque model of HIV persistence, comparing the function of CD20 CAR T cells between animals infected with simian/human immunodeficiency virus (SHIV) and uninfected controls. We focused on the potential of this approach to disrupt B-cell follicles (BCFs), exposing infected cells for immune clearance. In SHIV-infected animals, CAR T cells were highly functional with rapid expansion and trafficking to tissue-associated viral sanctuaries including BCFs and gut-associated lymphoid tissues (GALT). CD20 CAR T-cells potently ablated BCFs and depleted lymph node-associated T follicular helper (TFH) cells, with complete restoration of BCF architecture and TFH cells following CAR T-cell contraction. BCF ablation decreased the splenic SHIV reservoir but was insufficient for effective reductions in systemic viral reservoirs. Although associated with moderate hematologic toxicity, CD20 CAR T-cells were well tolerated in SHIV-infected and control animals, supporting the feasibility of this therapy in people living with HIV with underlying B-cell malignancies. Our findings highlight the unique ability of CD20 CAR T cells to safely and reversibly unmask TFH cells within BCF sanctuaries, informing future combinatorial HIV cure strategies designed to augment antiviral efficacy.

Efficacy of the combination of venetoclax and hypomethylating agents in the treatment of patients with primary, relapsed and/or refractory acute myeloid leukemia

Relevance and goals. Treatment of patients with acute myeloid leukemia has traditionally been highly intensive and includes induction therapy using cytarabine and anathracyclines. In addition to new opportunities in the treatment of acute myeloid leukemia, the problem of toxicity of high-intensity therapy in elderly and young somatically burdened patients is quite acute. International clinical trials of phases I-III demonstrated a combination of high efficacy and acceptable hematological toxicity of combinations of hypomethylating agents and venetoclax in the first line of therapy, as well as in the treatment of resistant forms and relapses of acute myeloid leukemia in the older age group, which contributed to the study of the effectiveness of combinations of hypomethylating agents and venetoclax in the treatment of similar groups of young comorbid patients. In this work, we evaluated the efficiency of a combination of hypomethylating agents and venetoclax and overall and disease-free survival in patients with acute myeloid leukemia in routine practice.Methods. In the period from October 2017 to December 2021 on the basis of the Department of Hematology No. 11 and the Department of Bone Marrow and Hematopoietic Stem Cell Transplantation No. 56 of the Botkin Hospital (Moscow, Russia) 33 patients with acute myeloid leukemia received venetoclax therapy in combination with decitabine or azacitidine: 14 (42%) men and 19 (58%) women, median age was 60 years (23–83 years). In 42% (14 of 33) of cases, the regimen was prescribed for resistant course or relapse of acute myeloid leukemia and in 61% (20 of 33) as induction therapy. Three patients (15%) out of 19 from the group of newly diagnosed acute myeloid leukemia received this treatment regimen in the first line, taking into account the ECOG status 3-4. By August 2022, 13 (39%) patients are alive, 20 (61%) people have died. Overall survival, the rate of complete remission and complete remission with incomplete recovery, the rate of achieving negativity of minimal residual disease, the frequency of hematological toxicity and infectious complications were assessed. Statistical data processing used: frequency analysis using contingency tables (Fisher's exact test), survival analysis using the Kaplan-Meier method.Results. Complete remission and complete remission with incomplete recovery were achieved in 72.72% (24 of 33) of patients. In the group of primary acute myeloid leukemia, remissions were observed in 80% (16 out of 20) of cases, in the group with resistant course or recurrence of acute myeloid leukemia in 67% (8 out of 12) (p = 0.3). Determination of minimal residual disease by flow cytometry after the 1st course was performed for 54.54% (18 of 33) patients, while negativity was stated in 84.2% (14 of 18 patients) cases. In both groups, the incidence of hematological toxicity and infectious complications are comparable to those according to the literature data. The median follow-up was 9.5 months (1–47). Median overall survival was 39 months, 2-year overall survival was 63%, and overall 4-year survival was 39%. The disease-free survival rate was 33%.Conclusion. The combination of hypomethylating agents and venetoclax showed good efficacy and fairly high overall survival in patients of all age groups, both for primary acute myeloid leukemia and for relapses and resistant forms, regardless of previous therapy. Given the moderate hematological toxicity, as well as the relatively low rates of infectious complications during therapy, including the rather low mortality rates in case of COVID-19 infection in comparison with those on the background of high-intensity courses of therapy for acute myeloid leukemia, this scheme can be widely used not only in patients of the older age group, but also in young comorbid patients.

Induction Regimen in High-Risk Neuroblastoma: A Pilot Study of Highly Effective Continuous Exposure of Tumor Cells to Radio-Chemotherapy Sequence for 1 Month. The Critical Role of Iodine-131-Metaiodobenzylguanidine.

Simple SummaryDespite the use of intensive chemotherapy, the prognosis of high-risk neuroblastoma continues to be dismal. Higher cure rates appear to be mainly correlated with the response to induction therapy. Nevertheless, in recent decades, there has been no significant improvement in the response rate to most induction treatments. The present induction regimen, of only one month duration, which includes iodine-131-metaiodobenzylguanidine (i.e., low-dose rate form of irradiation that persists in the tumor cells for a few weeks) allows for a highly effective continuous exposure of tumor cells to both chemotherapy and radiotherapy, at the time of maximal tumor cell sensitivity to treatment. Following future investigations, along the same line, a higher cure rate in patients with advanced neuroblastoma might be achieved.The prognosis of high-risk neuroblastoma (NB) continues to be poor. The early development of resistance often leads to disease recurrence. In the present study, an innovative induction regimen, including an intensive initial radio-chemotherapy sequence based on the use of iodine-131-metaiodobenzylguanidine (131-I-MIBG), was investigated. The duration of the regimen lasted only one month. Fifteen newly diagnosed patients aged >18 months with high-risk NB were treated with cisplatin, etoposide, cyclophosphamide, and vincristine, followed on day 10 by 131-I-MIBG (dose: 12–18.3 mCi/kg). Cisplatin and vincristine were administered on day 20 and 21 followed by the re-administration of vincristine, cyclophosphamide, and doxorubicin on day 29 and 30. Non-hematologic toxicity was not observed. Moderate hematologic toxicity was present probably attributable to chemotherapy. The evaluation of response was performed approximately 50 days after the initiation of treatment, yielding four complete responses, eight very good partial responses, one partial response, and two non-responses. Importantly, a complete metastatic response was achieved in 87% of patients. The present pilot study, which includes 131-I-MIBG, allows for a highly effective continuous exposure of tumor cells to both chemotherapy and radiotherapy. Furthermore, early high-dose chemotherapy followed by stem cell rescue may achieve high levels of tumor cell clearance and improve the prognosis of high-risk NB.

Prexasertib: an investigational checkpoint kinase inhibitor for the treatment of high-grade serous ovarian cancer

ABSTRACT Introduction Patients with high-grade serous ovarian cancer (HGSOC) have a poor prognosis, and current chemotherapy regimens for treating advanced disease are far from satisfactory. Prexasertib (LY2606368) is a novel checkpoint kinase inhibitor (CHK) under investigation for the treatment of HGSOC. Data from a recent phase II trial showed promising efficacy and safety results for treating wild-type BRCA HGSOC. Areas covered This article reviews the available data on the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of prexasertib in the treatment of HGSOC. Expert opinion Until now, prexasertib demonstrated clinical activity in phase I and II clinical trial for treating wild-type BRCA HGSOC, whereas its promising efficacy as monotherapy and combined with olaparib in BRCA-mutated HGSOC has been preliminary evidenced only in phase I studies. Compared to other drugs of the same class, prexasertib showed a better tolerability profile, causing moderate hematological toxicity. Further studies are needed to confirm efficacy and safety profiles of prexasertib in combined regimens. New early clinical trials may investigate prexasertib administered with programmed cell death ligand 1 (PD-L1) and PI3 K inhibitors due to the preclinical evidence of a synergic action.

Resistant Cytomegalovirus Infection After Renal Transplantation: Literature Review

BackgroundResistant cytomegalovirus (R-CMV) is an emerging problem in the renal transplantation population. The most frequent CMVs are high-resistance mutations (UL97 gene). MethodsWe describe our experience in management of R-CMV after renal transplant at our center (2012–2016). ResultsWe encountered 3 cases of R-CMV infection after renal transplant (all primary infections). All 3 patients received induction therapy with corticosteroids, tacrolimus, and mycophenolate mofetil. The first patient (basiliximab induction, preemptive CMV) developed CMV replication on day +53, which responded poorly both to standard-dose valganciclovir (vGCV) and high-dose ganciclovir (GCV) (creatinine clearance [CrCl] >70 mL/min; vGCV 900 mg twice daily for 50 days and GCV 7.5 mg/kg twice daily for 8 days). Hematologic toxicity occurred. The R-CMV test was positive and foscarnet (FOS) was initiated (90 mg/kg twice daily for 21 days). The second patient presented CMV infection (day +30, thymoglobulin induction, CMV prophylaxis), which was not controlled with the high dose (CrCl 23 mL/min; GCV 3.5 mg/kg twice daily and vGCV 900 mg twice daily), resulting in severe neutropenia. R-CMV was detected and FOS initiated (FOS 50 mg/kg twice daily for 7 days and 50 mg/kg every 2 days for 13 days). The third patient's infection occurred on day +22 (basiliximab induction, preemptive CMV). Standard-dose vGCV was uneffective (CrCl >70 mL/min, vGCV 900 mg twice daily) and it did not respond to the high dose (GCV 7.5 mg/kg twice daily and vGCV 2700 mg/d). Moderate hematologic toxicity occurred. R-CMV was diagnosed and FOS treatment begun (FOS 70 mg/kg per day for 2 weeks). ConclusionsResistant CMV infection may be severe due to viral infection and side effects of high-dose antiviral treatment. We presented 3 cases requiring the use of FOS in the absence of response or toxic effects from the usual treatment, with an optimal sustained response (temporary in case 2) and without serious side effects.

Применение малых доз децитабина с целью профилактики рецидива гемобластозов после аллогенной трансплантации гемопоэтических стволовых клеток: опыт одного центра

Relapse, graft-versus-host disease (GvHD) and GvHD-associated mortality are major obstacles to success of transplantation from allogenic donors in children with hematologic malignancies. Negative depletion of αβ (+) T-cells and CD19+ B lymphocytes, which permits to maintain mature donor-derived natural killer cells and γδ(+) T cells in the graft may improve GvHD control, but decrease GVL (graft versus leukemia) effect. Additional attempts at relapse prevention may be posttransplant use of hypomethylating agents. In this article, we report the results of a pilot study of decitabine safety in children with hematologic malignancies after allogeneic HSCT in our center. A total of 63 pediatric patients with hematologic malignancies underwent allogeneic HSCT between May 2012 and November 2013 enrolled in this study. Group «Decitabine+» consisted of 33 patients (14 – AML, 12 – ALL, 6 – UMML), group «Decitabine-» 31 patients (12 – AML, 17 – ALL, 2 – UMML). Decitabine was used in low dose 10 mg/m2/day during 5 days. 32 patients recieved 133 courses with median number of courses 4 (2–6). Hematologic toxicity included grade IV neutropenia in 35%, grade III in 33%, grade II in 19%; grade IV thrombocytopenia in 7,6%, grade III in 7%, infections complicated in 33%. In group «Decitabine+» 11 of the 32 patients experienced disease relapse, (mean of time to relapse 1 year), in group «Decitabine-» 9 patients (mean of time 0,42 y), p = 0,13. Decitabine can be administered to children on outpatient basis post-transplant with mostly moderate hematologic and mild visceral toxicity. Efficacy of post-transplant decitabine can be safely evaluated in a prospective controlled trial.

Phase 1b study with PEGylated human IL-10 (AM0010) with 5-FU and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC).

399 Background: The benefit of adding nal-irinotecan or oxaliplatin to 5-FU in second-line therapy for PDAC is relatively small and it has been refractory to immune therapies. The success and the durability of immunotherapy is thought to depend on the activation and expansion of intratumoral, tumor specific cytotoxic CD8+ T cells which are absent in most PDACs. AM0010 stimulates the survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Immune stimulation and prolonged stable disease in PDAC patients (pts) with single agent AM0010 was recently presented. Irinotecan may eliminate cytotoxic T cells. Treatment with platinum or 5-FU may activate immune responses to cancer and AM0010 has synergistic anti-tumor function with both in preclinical models. In this phase 1b clinical study, the efficacy of AM0010 with FOLFOX was explored in patients with PDAC. Methods: PDAC pts progressing on a median of 1 prior therapy (range 1-3) were treated daily with AM0010 in combination with FOLFOX (n=20). Tumor responses were monitored using irRC. Immune responses were monitored using analysis of serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Pretreatment samples were analyzed by IHC for tumor infiltration by CD8+ T cells. Results: G3/4 TrAEs included thrombocytopenia (55%), anemia (45%) and neutropenia (25%). There was no significant bleeding or febrile neutropenia. 16 pts had a objective tumor response assessment; 2 had an irCR, 1 an irPR, 10 had irSD. Eight remain on treatment, 2 for > 1 year. ORR was 15%, the DCR was 65%. The mPFS was 3.9 months. AM0010 increased serum Th1 cytokines and reduced mediators of chronic inflammation IL-23 and IL-17 and the immunosuppressive cytokine TGFb. AM0010 increased the number and proliferation of PD1+ activated CD8+ T cells and induced de-novo oligoclonal expansion of T cell clones without affecting total lymphocyte counts. Conclusions: AM0010 with FOLFOX is well tolerated with moderate hematological toxicity in patients with PDAC. The observed immune activation including CD8+ T cell activation and prolonged objective responses are encouraging and will be explored in a phase 3 trial starting in 2016.

Four Cases of Lenalidomide-Associated Immune Thrombocytopenia

IntroductionHematologic neoplasms are associated with an increased incidence of autoimmune events, particularly evident in non‐Hodgkin lymphomas (NHL) and especially chronic lymphocytic leukemia (CLL); until now only few cases have been described in patients affected by multiple myeloma (MM) and other plasma cell disorders. The introduction of new drugs, in particular immunomodulatory drugs (IMiDs), could increase the risk of these complications.Herein we describe four cases of immune thrombocytopenia (ITP) occurred during Lenalidomide (LEN) therapy in 3 patients affected by MM and 1 with light‐chain amyloidosis.Case reportsCase 1. A 66‐year old woman with relapsed IgGk MM started 2th line treatment with LEN/DEX 25 mg/d-20 mg/w. During the first 5 cycles she presented moderate hematologic toxicity which resolved after dose reduction (LEN 15 mg/d). A severe and isolated thrombocytopenia appeared after 5th cycle with patient in good partial remission (PR) for MM. A bone marrow evaluation showed absence of plasma cells and abundant megakaryocytes leading to a diagnosis of ITP. LEN was interrupted and steroid therapy (prednisone 1 mg/Kg) and IV Ig infusion administered, obtaining a transient good response (from 17 to 114 x 109/l). LEN was then restarted at lower dosage but a month after, while myeloma still was in good response, ITP relapsed complicated by intracranial hemorrhage and was successfully treated with IV Ig; Len was definitely interrupted. At the third relapse Rituximab (750 mg/w x 4 weeks) was administered with only minimal increase of platelet count (Fig 1). Afterwards, the patient died due to rapid MM progression.Case 2. A 76‐year old woman with relapsed IgGλ MM started 2th line treatment with LEN 15 mg. After the 3rd cycle, having obtained a very good partial remission (VGPR), she presented with grade 3 thrombocytopenia which did not ameliorate with LEN suspension and resolved only after introduction of steroid, thus supporting ITP diagnosis. She underwent a 4th cycle of LEN/DEX maintaining a normal platelet count but then LEN was interrupted due to rapid MM progression. (Fig 2).Case 3. A 78‐year old woman with renal amyloidosis in IgAλ gammopathy started a 2nd line treatment with LEN/DEX 15 mg/d-20 mg/w with a significant reduction in proteinuria. During the 6th cycle she presented with diffuse purpura and a platelet count of 18x109/L. She received platelet transfusion and bone marrow evaluation showed abundant megakaryocytes supporting the diagnosis of ITP. Furthermore anti‐platelet antibodies search resulted positive. Steroid therapy was started with partial response on platelet count but the patient remained steroid‐therapy dependent.Case 4. A 66‐year‐old woman affected by MM started a 2th‐line treatment with LEN‐DEX 25 mg/d-20 mg/w. After the third cycle, being the patient in PR, a isolated grade 3 thrombocytopenia developed, persisting despite discontinuation of LEN. Viral infections were excluded and antiplatelet antibodies search resulted positive. Therefore she started steroid therapy (prednisone 1 mg/Kg) with an progressive increase of platelet count from 44 to 80x109/L after a month of therapy, that is ongoing. Lenalidomide has not yet been restarted.DiscussionWe report four cases of ITP developing during LEN therapy with the characteristics of ITP. None of these patients had a history of previous autoimmune events, the decline of platelet count was rapid and other causes of thrombocytopenia were excluded or unlikely in all the cases. Furthermore diagnosis was supported by consistent bone marrow evaluation in two cases. Considering the temporal association in these four cases, the ITP mechanism may be related to the immunomodulation and T‐cell activation caused by LEN.Even if further other studies are needed, it seems reasonable to consider a possible association between LEN and autoimmune phenomena, in particular ITP. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Utility of day 8 blood tests on platinum plus vinorelbine regimen.

Background The combination of cisplatin or carboplatin with vinorelbine is one of the standard regimens in non-small-cell lung cancer. Some studies have shown that the hemogram on day-8 could be avoided in patients with cisplatin. However, carboplatin had not been studied and is considered to be more myelotoxic than cisplatin. Objective To quantify the incidence of thrombocytopenia, anemia, neutropenia and impaired liver and renal tests on day 8 in patients receiving a doublet protocol including a platinum and vinorelbine. Method The incidence of blood test abnormalities has been quantified in all patients who had received at least one course of cisplatin or carboplatin plus vinorelbine from January 14-December 14. Results Eighty-nine patients and 314 courses on day-8 were evaluated. Moderate or severe hematological toxicity was observed in 5.7% courses. Dose was skipped in 1.3% courses related to neutropenia. Renal and liver impairment were not shown. Delayed and reduced doses and early discontinued treatment on day-8 were not caused by blood test abnormalities. Conclusions Blood tests might be spared on day-8 depending on the individual characteristics, above all in patients with carboplatin.

Intermediate Results of Treatment of Primary Mediastinal Large В-Cell Lymphoma with Da-Epoch-R Regimen

ABSTRACT Aim: To estimate efficacy and toxicity of R-DA-EPOCH regimen in patients with primary mediastinal (thymic) large B-cell lymphoma (PMBL). Methods: The studied group included 22 patients with newly diagnosed PMBL. Median age was 34 years, 16 were females (72,8%) and 6 were mails (27,2%). Primary and post treatment assessment of disease included PET/CT or CT of neck, chest, abdomen and pelvic. In 61,5% of patient was early stage (І-ІІ) of disease, 93,3% of patients had greatest size of the tumor mass in mediastinum more than 10 cm. The tumor pleurisy, pericarditis and lungs lesions were revealed in 46,5%, 52% and 30,7%, respectively. All patients received 6 cycles of R-DA-EPOCH regimen. Patients who achieved complete metabolic response received mediastinal radiation therapy (30 Gy) or were under observation. Results: Response assessment performed after the completion of 6th cycles of chemotherapy. 19 patients have already completed treatment plan. 2 patients were exclude from study due to diseases progression (one of them had CNS lesion after 3rd cycle of chemotherapy, second patient had rapid increase of mediastinal mass after 6 cycle). Overall response rate was 89,4%. Complete response was achieved in 14 patients (73,6%). PET/CT was performed in 16 patients. Complete morphologic regression but with residual metabolic activity of residual mass was revealed in 5 patients (31,3%). Treatment was associated with moderate hematological toxicity: anemia grade 4 observed in one case (5,2%), febrile neutropenia requiring hospitalization in 2 patients (10,5%), and one of them had infection associated with venous port. Thrombocytopenia grade 3-4 was not observed. All detected cases of non-hematological toxicity were grade 1 or 2. Diarrhea, nausea, stomatitis, neuropathy were observed in 5,2%, 10,5%, 36,8% and in 31,6% of cases, respectively. Conclusions: Our results indicate that R-DA-EPOCH has a high cure rate in patients with PMBL, which allows to achieve good response in 89,4% cases. Such treatment associated with moderate hematological and non-hematological toxicity. Further continuation of study is needed to estimate and analyze long-term results of therapy. Disclosure: All authors have declared no conflicts of interest.

Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified liposarcoma.

10512 Background: Approximately 90% of well-differentiated / de-differentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase II study demonstrated that treatment with PD0332991 (200mg daily x 14d every 21d) results in clinical benefit in WD/DDLS but moderate hematologic toxicity (48% Grade 3/4 neutropenia; dose reduction in 24%). Aiming to reduce toxicity, we conducted a phase II study to assess progression-free survival (PFS) and toxicity with PD0332991 at a new dose and schedule, 125mg daily x 21d every 28d. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age ≥ 18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein expression by immunohistochemistry (≥1+). Pts received oral PD0332991 at 125mg daily for 21 days in 28-day cycles. The primary endpoint was PFS at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD0332991 would be considered to have activity in WD/DDLS. Results: 29 pts were enrolled and 25 were evaluable for the primary endpoint. Median age was 62 (range 42-85); 55% were male; median ECOG score was 0 (range 0-1). PFS at 12 weeks was 56% (14/25 patients; 90% CI 41-100%), and thus the study significantly exceeded its primary endpoint. Median PFS was 23.6 weeks (95% CI: 11.6 to Not Reached). There was 1 confirmed partial response lasting > 1 year. Grade 3 and 4 adverse events included anemia (grade 3, 21%), thrombocytopenia (grade 3, 7%; grade 4, 3%), and neutropenia (grade 3, 34%). Dose reduction was required in only 1 patient. Conclusions: In patients with WD/DDLS with CDK4 amplification, PD0332991 treatment was associated with a favorable PFS and objective tumor response. This dose and schedule appears active and may have less toxicity than 200mg x 14d. The 125mg x 21d schedule warrants evaluation in a phase 3 study. Clinical trial information: NCT01209598.

Therapeutic efficiency of everolimus and lapatinib in xenograft model of human colorectal carcinoma with KRAS mutation

KRAS mutation is a negative predictive prognostic factor during metastatic colorectal cancer treatment with antiepidermal growth factor receptor antibodies. For affected patients, new therapeutics must be explored. Our objective was to study efficacy of two drugs with different mechanisms of action, everolimus (mTOR inhibitor) and lapatinib (tyrosine kinase inhibitor), in a mouse xenograft model. We chose a model obtained after engraftment of a tumor originating from a human tumor collection. The patient was affected by a metastasis colorectal carcinoma resistant to cetuximab with KRAS mutation. From a previous study in mice, we know that everolimus is a P-glycoprotein (P-gp) substrate and that a lapatinib pretreatment increases significantly (2.6-fold) everolimus AUC by inhibiting its intestinal P-gp efflux. We hence tested the effect of these drugs alone or combined. Mice bearing the xenografts were divided in four groups: control, lapatinib, everolimus, and L/E group (L/E: 2 days of lapatinib 200 mg/kg and then 3 days of everolimus 1 mg/kg). Tumor volumes and treatment toxicities were evaluated. Sixteen days after treatment initiation, the group L/E was the first one in which tumor volume average was significantly lower than the one of control group (193 ± 90 vs. 395 ± 171 mm(3) ; P = 0.0025). After 4 weeks of treatment, inhibition of tumor growth in lapatinib, everolimus, and L/E groups reached, respectively, 49, 53, and 57%. Each drug showed significant antitumor activity. Only moderate hematologic toxicity signs were observed. These results lead to new perspectives for new oral drugs in metastatic KRAS-mutated colorectal cancer resistant to standard chemotherapy.

A Phase II Trial of Neoadjuvant Gemcitabine, Epirubicin, and Docetaxel as Primary Treatment of Patients With Locally Advanced or Inflammatory Breast Cancer

Background Three-drug regimens containing gemcitabine, an anthracycline, and a taxane produce response rates of 70%-90% in patients with metastatic breast cancer (MBC) although accompanied by considerable hematologic toxicity. We explored the combination of gemcitabine/epirubicin/docetaxel as neoadjuvant therapy. Docetaxel was administered weekly to decrease myelosuppression. Patients and Methods A total of 110 patients with locally advanced or inflammatory breast cancer received neoadjuvant gemcitabine 800 mg/m 2 intravenously (I.V.) days 1 and 8, epirubicin 75 mg/m 2 I.V. day 1, and docetaxel 30 mg/m 2 I.V. days 1 and 8, repeated every 21 days for 4 cycles. Then patients had either mastectomy or breast conservation surgery, and pathologic treatment responses were assessed. After surgery, 4 cycles of adjuvant gemcitabine 1000 mg/m 2 I.V. days 1 and 8 and docetaxel 35 mg/m 2 I.V. days 1 and 8 were administered at 21-day intervals. After patients completed chemotherapy, locoregional radiation therapy and/or anti-estrogen therapy was administered per standard guidelines. Results Treatment with 4 cycles of neoadjuvant gemcitabine, epirubicin, and weekly docetaxel resulted in an objective response in 79 of 110 patients enrolled (72%; 95% CI, 63-80%). Twenty of 103 patients (19%) who had surgery had pathologic complete response (pCR). Moderate hematologic toxicity was evident during neoadjuvant therapy, with grade 3/4 neutropenia in 41% and febrile neutropenia in 11% of the patients. Protocol-specified dose modifications were required in 35% of the patients, and 58% of the patients used myeloid growth factors. Conclusion The pCR rate of 19% achieved with gemcitabine, epirubicin, and weekly docetaxel confirms previous reports with similar 3-drug regimens. The use of a weekly schedule of docetaxel did not appear to reduce the incidence of grade 3/4 hematologic toxicity.

A Phase II Study of Cetuximab/Irinotecan in Patients with Heavily Pretreated Metastatic Colorectal Cancer: Predictive Value of Early Specific Toxicities

This study was designed to evaluate the predictive value of early specific toxicities on efficacy of weekly irinotecan/cetuximab administered as salvage therapy in patients with metastatic colorectal cancer (CRC) refractory to oxaliplatin and irinotecan. Seventy patients received a regimen composed of weekly irinotecan 125 mg/m2 as a 1-hour intravenous infusion and cetuximab 400 mg/m2 infused over 2 hours as the initial dose and 250 mg/m2 infused over 1 hour for subsequent administrations. A single treatment cycle was composed of 4 weekly irinotecan infusions followed by 2 weeks of rest. The predictive value of adverse events (AEs) attributable to cetuximab (rash) and major toxicities attributable to irinotecan (gastrointestinal [GI] and hematologic) were observed after the first cycle of treatment and, therefore, correlated to activity and efficacy of cetuximab and weekly irinotecan. Sixty-six of 70 patients received >or= 1 cycle of chemotherapy and were therefore evaluable for response. Overall, toxicity observed was generally mild and manageable. According to an intent-to-treat analysis, a partial response was exhibited in 15.7% of patients, with a median progression-free survival (PFS) and median overall survival time of 4 months and 9 months, respectively. As expected, PFS (P = .01) and median survival (P = .04) correlated strongly with the presence and severity of the rash. Surprisingly, the presence of at least moderate hematologic and GI toxicity was associated with improved PFS (P = .03). Our data suggest that irinotecan-induced AEs might predict a better outcome in advanced CRC. This finding would identify a different subset of patients-those likely to benefit from a renewed sensitivity to irinotecan induced by cetuximab.

Phase II Trial of T138067, a Novel Microtubule Inhibitor, in Patients with Metastatic, Refractory Colorectal Carcinoma

This study was conducted before the approval of oxaliplatin, cetuximab, and bevacizumab and was designed to evaluate a novel microtubule targeting agent, T138067, in patients with metastatic colorectal cancer (CRC) previously treated with irinotecan and 5-fluorouracil. Patients from 3 institutions were enrolled over 4 months and treated with T138067 on days 1, 8, and 15 of a 21-day cycle. Disease evaluation was performed after 9 weeks. Treatment was tolerable with moderate hematologic and gastrointestinal toxicity. Neurotoxicity, an expected side effect, was minimal. Among 23 evaluable patients, there were no responses. Median time to tumor progression was 1.4 months and median survival was 9.3 months. T138067 at this dose and schedule was well tolerated by patients with CRC. However, there was no evidence of clinical activity for T138067 in 5-fluorouracil/irinotecan-refractory CRC. The long median survival likely reflects availability of other agents and/or patient selection.

Phase II trial of gemcitabine and carboplatin, plus trastuzumab in HER2+ patients as first line therapy in metastatic breast cancer

10590 Background: Gemcitabine (G) and carboplatin (C) demonstrate significant preclinical synergy together as well as in combination with trastuzumab (H) in metastatic breast cancer (MBC) pts. This multicenter phase II trial evaluates the efficacy and safety of G + C with trastuzumab in HER2 + pts as 1st line therapy in MBC. Methods: Eligibility requirements: females > 18 with no prior regimens for MBC, ECOG 0–2, RECIST bidimensional disease, and adequate organ function. FISH HER2 + pts received H with GC. Treatment: G 1,000 mg/m2 D1& 8 with C AUC 5 D1 in the first 20 pts. Following a toxicity assessment revealing significant myelosuppression, C was administered in subsequent pts at AUC 4. 14 HER2+ pts received H 8 mg/kg loading dose followed by 6 mg/kg q21 days. Pts were evaluated for response after 9 weeks; treatment continued until progression or toxicity except in HER2+ pts who received up to 6 cycles GCH followed by single agent H. Results: Between 11/03 & 11/05, 45 pts have been treated: median age 55 for GC, 65 for GCH, ECOG 0/1 22/23. 19 pts were chemonaive. 26 pts received prior adjuvant chemotherapy: 20 pts adjuvant anthracyclines (A) & taxanes (T), 3 only prior A and 3 prior T. 73% had 2 or more metastatic sites of disease. 31 pts received GC & 14 pts received GCH. 18 of 41 evaluable pts (44%) had objective responses (PR 16, CR 2) with 17 pts (42%) exhibiting SD & 6 pts PD (15%). 91% of AT pretreated pts demonstrated SD or better. 9 remain on study. 6 went off study due to heme related toxicities and 9 due to MD discretion [4 max benefit, 3 XRT]. Median # of cycles was 5. Combined G3/4 hematologic toxicity was notable for 66% neutropenia (only 1 FN), 55% thrombocytopenia, and 32% anemia, predominately occurring at the carboplatin AUC 5 dose level. Transfusions of PRBCs and plts were administered in 14 and 8 pts respectively. Nonhematologic toxicity was minimal and remarkable for G3/4 fatigue in 20%. Conclusions: In FISH HER2+ pts, the addition of trastuzumab to GC yielded a 50% RR, with no evident cardiotoxicity. The combination of gemcitabine with carboplatin AUC 4 is active, albeit with moderate hematologic toxicity, warranting further exploration of alternate GC ± H schedules in breast cancer. [Table: see text]

Efficacy and Safety of Alemtuzumab in Patients with Relapsed B-Cell Chronic Lymphocytic Leukemia after Autologous Stem Cell Transplantation.

This phase II study investigated the efficacy and safety of alemtuzumab (Campath-1H), as treatment to achieve a second minimal residual disease (MRD) negative complete remission, in patients with relapsed B-cell chronic lymphocytic leukemia (B-CLL) after autologous stem cell transplantation (ASCT). Only patients who had experienced a posttransplantation MRD negative status and with a low tumour burden at relapse were eligible for the study. Eleven patients were treated. Nine patients were Binet Stage A and two patients had converted to an MRD positive status. The median time from ASCT was 36 months (range, 15–66 months). Alemtuzumab was administered as a 30 mg intravenous injection three times weekly for a maximum of 12 weeks. All patients received valacyclovir and trimethoprim/sulfamethoxazole as infection prophylaxis during therapy and 6 months after. Cytomegalovirus (CMV) reactivation was monitored weekly using a blood antigen test. Patients with Binet stage A were evaluated according to National Cancer Institute (NCI) criteria. MRD assessment was performed in complete responders and the two MRD relapses in blood and bone marrow using sensitive techniques as MRD Flow (Rawstron et al, Blood 2001, 98: 35) and nonspecific allele IgH PCR. Among nine patients assessed for disease response by NCI criteria, two (22%) achieved a partial response and five (55%) a complete remission (overall response rate [ORR], 77%). The overall median response duration was 9 months (range, 4–18+ months) and 12 months (range, 6–18+ months) for complete responders. Five patients (45%) converted to a phenotypic and molecular complete remission, with a median response duration of 6 months (range, 4–18+ months). Two patients remained in MRD negative complete remission after therapy at 18+ and 12+ months, respectively. The treatment-free median survival has not been reached for complete responders, with a median follow-up of 14 months. All patients were evaluable for toxicity. WHO grade 1–2 infusion-related reactions were observed in up to 90% of patients with the initial escalating dose. A moderate hematological toxicity was reported, except for platelets. Frequency of grade 3–4 events during therapy were as follows: 27% of anemia, 18% of neutropenia and 54% of thrombocytopenia. A delayed-onset neutropenia occured in three patients, up to 2 months after completion of treatment. Grade 2 infections were observed in six patients (54%). Only one patient experienced a major infection. Two patients (18%) developed CMV reactivation, CMV disease was successfully prevented by treatment with oral ganciclovir, without discontinuing alemtuzumab therapy. Alemtuzumab has demonstrated activity and safety in relapsed B-CLL patients after ASCT with an ORR of 77% and an MRD negativity of 45%. However, the question of maintaining a durable MRD negative complete response remains posed.

A comparative analysis of low-dose metronomic cyclophosphamide reveals absent or low-grade toxicity on tissues highly sensitive to the toxic effects of maximum tolerated dose regimens.

The survival benefits of traditional maximum tolerated dose (MTD) cytotoxic therapy have been modest for the treatment of most types of metastatic malignancy and, moreover, often come with increased acute and chronic toxicity. Recent studies have demonstrated that the frequent administration of comparatively low doses of cytotoxic agents, with no extended breaks [low-dose metronomic (LDM) chemotherapy], may not only be at least as efficient as MTD therapy but also less toxic. This coincides with an apparent selectivity for "activated" endothelial cells of the tumor vasculature. However, the impact of LDM chemotherapy on the most sensitive target cell populations normally affected by MTD therapy (i.e., bone marrow progenitors, gut mucosa, and hair follicle cells) has not been analyzed in experimental detail. Therefore, we compared effects of LDM and MTD cyclophosphamide (CTX) on bone marrow and gut mucosa. Furthermore, we studied the potential impact of LDM CTX on angiogenesis in the context of wound healing and evidence of organ toxicity. We show absent or moderate hematologic and intestinal toxicity of LDM as opposed to MTD CTX. Of note was the finding of sustained lymphopenia, which is not unexpected given the use of CTX as immunosuppressive drug. There was no negative impact on wound healing or evidence of organ toxicity. LDM offers clear safety advantages over conventional MTD chemotherapy and therefore would appear to be ideal for long-term combination therapy with targeted antiangiogenic drugs.

A phase II study of liposomal lurtotecan (OSI-211) in patients with topotecan resistant ovarian cancer

Objective. To determine the safety and efficacy of a novel topoisomerase I inhibitor, liposomal lurtotecan, in patients with topotecan resistant ovarian cancer. Methods. The trial was an open-label phase II study for patients stratified by resistance to either single agent topotecan or to a prior topotecan-containing regimen. Liposomal lurtotecan was delivered at a dose of 2.4 mg/m 2 on Days 1 and 8 of a 21-day cycle. Dose escalations and reductions were allowed based on hematologic toxicity. Patients were evaluated every two cycles for response to liposomal lurtotecan. Results. Twenty-two women were accrued, with 16 women resistant to single agent topotecan and 6 women resistant to topotecan given in combination with a second chemotherapy agent. Hematologic toxicity consisted of mild to moderate thrombocytopenia, anemia, and neutropenia with mild to moderate gastrointestinal toxicity and fatigue. There were no responses, although eight patients had stable disease. Conclusions. Liposomal lurtotecan at this schedule demonstrates moderate hematologic toxicity and no evidence of clinical activity in a group of heavily pretreated women previously exposed to the topoisomerase I inhibitor topotecan. The study of this agent in alternative patient populations or with alternative schedules is ongoing.

Phase I and pharmacokinetic study of KW-2149 given by 24 hours continuous infusion

KW-2149 is a new mitomycin C (MMC) analog, forming DNA-DNA and DNA-protein crosslinking 20-fold more effectively than MMC. Because of its equal or superior in vitro and in vivo activity compared to MMC, a phase I study was initiated with an intravenous bolus injection every three weeks. This study was interrupted after dose escalation from 5 mg/m2 to 100 mg/m2 because of subacute and dose dependent pulmonary toxicity. Because of the lack of other end-organ toxicity, the moderate hematological toxicity and the observed antitumor effect, a second phase I study was initiated with a 24 hour continuous infusion. The starting dose was 50 mg/m2 and further escalation depended on observed pulmonary toxicity. Four patients were entered into this study and the received in total 17 courses. Toxicity was again mainly restricted to the lungs with one patient suffering grade 2 dyspnoe and another one grade 1 dyspnoe. Three patients had a substantial change in the carbon monoxide (CO) diffusion capacity. Pharmacokinetic data from these patients showed very low plasma levels both for KW-2149, as for both known metabolites M-16 and M-18. This study demonstrates that pulmonary toxicity continues to occur with KW-2149, in spite of the assurance of low plasma levels of both the parent compound and the known metabolites. The interesting activity of this compound has stimulated further in-depth research towards mechanisms of pulmonary toxicity and means of preventing them.