Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma in patients with concomitant chronic lymphocytic leukemia.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. PATIENTS AND METHODS: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. RESULTS: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. CONCLUSIONS: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial.

BACKGROUND: The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment. PATIENTS AND METHODS: Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors. RESULTS: ORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib. CONCLUSION: Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01028222.

Bowel perforation in intestinal lymphoma: incidence and clinical features.

BACKGROUND: Perforation is a serious life-threatening complication of lymphomas involving the gastrointestinal (GI) tract. Although some perforations occur as the initial presentation of GI lymphoma, others occur after initiation of chemotherapy. To define the location and timing of perforation, a single-center study was carried out of all patients with GI lymphoma. PATIENTS AND METHODS: Between 1975 and 2012, 1062 patients were identified with biopsy-proven GI involvement with lymphoma. A retrospective chart review was undertaken to identify patients with gut perforation and to determine their clinicopathologic features. RESULTS: Nine percent (92 of 1062) of patients developed a perforation, of which 55% (51 of 92) occurred after chemotherapy. The median day of perforation after initiation of chemotherapy was 46 days (mean, 83 days; range, 2-298) and 44% of perforations occurred within the first 4 weeks of treatment. Diffuse large B-cell lymphoma (DLBCL) was the most common lymphoma associated with perforation (59%, 55 of 92). Compared with indolent B-cell lymphomas, the risk of perforation was higher with aggressive B-cell lymphomas (hazard ratio, HR = 6.31, P < 0.0001) or T-cell/other types (HR = 12.40, P < 0.0001). The small intestine was the most common site of perforation (59%). CONCLUSION: Perforation remains a significant complication of GI lymphomas and is more frequently associated with aggressive than indolent lymphomas. Supported in part by University of Iowa/Mayo Clinic SPORE CA97274 and the Predolin Foundation.

Normal ageing is associated with an increase in Th2 cells, MCP-1 (CCL1) and RANTES (CCL5), with differences in sCD40L and PDGF-AA between sexes.

We have observed T helper type 2 (Th2) polarization of systemic immunity in patients with metastatic malignant melanoma. We hypothesized that similar changes in systemic immunity occur with ageing and may be permissive for the development of melanoma. We analysed the peripheral blood of 389 healthy blood donors. All subjects were profiled for peripheral blood T cell and B cell subsets, and 58 of these subjects were profiled for antigen-specific cytotoxic T cell subsets [cytomegalovirus (CMV), influenza and melanoma antigen recognized by T cells 1 (MART-1)]. Ninety-five separate healthy subjects underwent profiling of 42 plasma cytokines. Ageing was associated positively with CD4(+) CD294(+) Th2 cells, and associated negatively with CD3(+) T cells, cytotoxic T cells and T helper cells. Ageing was also associated negatively with CMV-, influenza- and MART-1-specific naive and CD8(+) T cells. There were significant increases in plasma monocyte chemotactic protein 1 (MCP-1) (CCL1) and regulated upon activation normal T cell expressed and secreted (RANTES) (CCL5) with age. We observed differences in cytokine profiles between males and females; specifically, women had higher levels of sCD40L and PDGF-AA. In summary, we demonstrated in healthy blood donors that ageing was associated with an increase in cellular Th2 bias and a decline in total numbers of T cells. Additionally, there was an increase in MCP-1 and RANTES with ageing. Women had higher levels of sCD40L and PDGF-AA than men.

Metastatic malignant melanoma.

Metastatic malignant melanoma is an incurable malignancy with extremely poor prognosis. Patients bearing this diagnosis face a median survival time of approximately 9 months with a probability of surviving 5 years after initial presentation at less than 5%. This is contrasted by the curative nature of surgical resection of early melanoma detected in the skin. To date, no systemic therapy has consistently and predictably impacted the overall survival of patients with metastatic melanoma. However, in recent years, a resurgence of innovative diagnostic and therapeutic developments have broadened our understanding of the natural history of melanoma and identified rational therapeutic targets/strategies that seem poised to significantly change the clinical outcomes in these patients. Herein we review the state-of-the-art in metastatic melanoma diagnostics and therapeutics with particular emphasis on multi-disciplinary clinical management.

Infusion of autograft natural killer cell/CD14+HLA-DRDIM cell ratio predicts survival in lymphoma post autologous stem cell transplantation.

The infusion of autograft absolute lymphocyte count (A-ALC) and autograft natural killer cells (A-NKC) are prognostic factors for overall survival (OS) and PFS in non-Hodgkin's lymphoma (NHL) patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). The human monocytic CD14+HLA-DRDIM cells are associated with worse prognosis in NHL. Thus, we investigated whether the autograft A-NKC/A-CD14+HLA-DRDIM ratio predicts survival in NHL. In a total of 111 NHL patients, we analyzed apheresis collection samples for the content of A-NKC and A-CD14+HLA-DRDIM. With a median follow-up of 57.2 months (range: 2.1-84.6 months), patients with an A-NKC/A-CD14+HLA-DRDIM ratio of ⩾0.29 experienced superior OS (5-year OS rates of 84% (95% confidence interval (CI), 72-91%) vs 48% (95% CI, 34-62%), P<0.0002, respectively) and PFS (5-year PFS rates of 59% (95% CI, 47-71%) vs 32% (95% CI, 20-48%), P<0.002, respectively). Multivariate analysis revealed that A-NKC/A-CD14+HLA-DRDIM ratio was an independent predictor for PFS (hazard ratio (HR)=0.56, 95% CI, 0.32-0.96, P<0.03) and OS (HR=0.34, 95% CI, 0.16-0.68, P<0.002). The A-NKC/A-CD14+HLA-DRDIM ratio provides a platform to target specific autograft immune effector cells to improve clinical outcomes in NHL patients undergoing APBHSCT.

Absolute lymphocyte count recovery after induction chemotherapy predicts superior survival in acute myelogenous leukemia.

Absolute lymphocyte count (ALC) recovery postautologous stem cell transplantation is an independent predictor for survival in acute myelogenous leukemia (AML). The role of ALC recovery after induction chemotherapy (IC) in AML is unknown. We hypothesize that ALC recovery after IC has a direct impact on survival. We have now evaluated the impact of ALC recovery after IC on overall survival (OS) and leukemia-free survival (LFS) in 103 consecutive, newly diagnosed AML patients treated with standard IC and consolidation chemotherapy (CC) from 1998 to 2002. ALC recovery was studied at days 15 (ALC-15), 21 (ALC-21), 28 (ALC-28) after IC and before the first CC (ALC-CC). Superior OS and LFS at each time point were observed with an ALC-15, ALC-21, ALC-28, and ALC-CC > or = 500 cells/microl. Patients with an ALC > or = 500 cells/microl at all time points vs those who did not have superior OS and LFS (not reached vs 13 months, P<0.0001; and not reached vs 11 months, P<0.0001, respectively). Multivariate analysis demonstrated ALC > or = 500 cells/microl at all time points to be an independent prognostic factor for survival. Our data suggest a critical role of lymphocyte (immune) recovery on survival after IC in AML.

Early lymphocyte recovery after autologous stem cell transplantation predicts superior survival in mantle-cell lymphoma.

Autologous stem cell transplantation (ASCT) is an effective treatment strategy for mantle-cell lymphoma (MCL) demonstrating significantly prolonged progression-free survival (PFS) when compared to interferon-alpha maintenance therapy of patients in first remission. The study of absolute lymphocyte count at day 15 (ALC-15) after ASCT as a prognostic factor in non-Hodgkin lymphoma (NHL) included different lymphoma subtypes. The relationship of ALC-15 after ASCT in MCL has not been specifically addressed. We evaluated the impact of ALC-15 recovery on survival of MCL patients undergoing ASCT. We studied 42 consecutive MCL patients who underwent ASCT at the Mayo Clinic in Rochester from 1993 to 2005. ALC-15 threshold was set at 500 cells/microl. The median follow-up after ASCT was 25 months (range, 2-106 months). The median overall survival (OS) and PFS times were significantly better for the 24 patients who achieved an ALC-15 >or=500 cells/microl compared with 18 patients with ALC-15 <500 cells/microl (not reached vs 30 months, P<0.01 and not reached vs 16 months, P<0.0006, respectively). Multivariate analysis demonstrated ALC-15 to be an independent prognostic factor for OS and PFS. The ALC-15 >or=500 cells/microl is associated with a significantly improved clinical outcome following ASCT in MCL.

Apheresis instrument settings influence infused absolute lymphocyte count affecting survival following autologous peripheral hematopoietic stem cell transplantation in non-Hodgkin's lymphoma: the need to optimize instrument setting and define a lymphocyte collection target.

Autograft absolute lymphocyte count (A-ALC) is an independent prognostic factor for survival after autologous peripheral blood hematopoietic stem cell transplantation (APHSCT) for non-Hodgkin's lymphoma (NHL). Factors enhancing A-ALC collections are unknown. We hypothesize that apheresis instrument settings could affect A-ALC. Data from 127 NHL patients collected from 15 January 1999 to 30 July 2004 using a single apheresis instrument (COBE Spectra (SP), Baxter Amicus (AM), and CS3000 Plus (CS)) were analyzed. The primary end point of the study was to assess the correlation between apheresis instrument settings and A-ALC. The secondary end point was to determine the effect of apheresis instrument on survival post-APHSCT. Patients collected using SP achieved higher A-ALC compared to AM (with modified settings) or CS (P<0.05) and demonstrated superior overall (OS) and progression-free survival (PFS) (P<0.03). Multivariate analysis demonstrated A-ALC and not the apheresis instrument as an independent prognostic factor for OS and PFS, cancelling the prognostic effect of the apheresis instruments observed in the univariate analysis. The survival advantage observed by SP was from the higher A-ALC collected compared to AM and CS. These data suggest that apheresis instrument settings should be optimized to collect CD34(+) cells as well as an A-ALC target, with direct impact on survival post-APHSCT.

Role of natural killer and T-cells in interferon induced inhibition of spontaneous metastases of the B16F10L murine melanoma.

We have previously demonstrated that interferon (IFN) treatment of mice bearing the spontaneously metastasizing B16F10L murine melanoma on days -5 to -1 prior to surgical removal (day 0) of the primary tumor resulted in survival of greater than 50% of treated mice. The antitumor effect was correlated with an early increase of natural killer (NK) cell cytotoxicity followed by a later developing specific cytolytic T-cell response. The purpose of this study was to establish definitively the roles of NK, CD4, and CD8 cells as mediators of the antitumor/antimetastatic effects of IFN treatment by administration of anti-asialo-GM1, anti-L3T4, and/or anti-Lyt-2 antisera. Depletion of NK cells, alone or in combination with T-cells, eliminated the protective effect of IFN treatment. Depletion of both CD4 and CD8 cells, however, did not significantly alter the therapeutic effect of IFN therapy. Collectively, these data conclusively demonstrated the importance of NK cells as mediators of the IFN induced antitumor state. However, in mice depleted of CD4 cells alone, the protective effect of IFN was eliminated, in spite of the presence of intact NK cells. In vitro analysis of NK cytotoxicity on day 1 after surgery demonstrated (a) a lack of IFN induced stimulation of NK activity in CD4 depleted mice and (b) a significant increase in both baseline and IFN induced NK cytotoxicity in CD8 depleted mice. These data suggested a CD8 cell mediated inhibition of NK activity/stimulation in CD4 depleted mice, possibly responsible for the lack of response to IFN therapy in that group. These results demonstrate the importance of not only individual components of the immune system but also the interaction of these components in both the natural and IFN induced control of spontaneous B16F10L metastases.

Interferon-induced inhibition of Moloney sarcoma virus-transformed cells: requirement for T-cells.

We previously demonstrated that although natural killer (NK) cells participated in interferon (IFN)-induced inhibition of growth of the Moloney sarcoma MSC cell tumor, the need for NK cells could be circumvented by using a small tumor cell challenge or an increased amount of IFN. These studies were performed in normal, euthymic mice. The role of T-cells remained undefined. In the present study, nude mice were used to evaluate the role of T-cells. Investigation of various treatment regimens revealed that IFN could not totally inhibit tumor growth in nude mice. A significant delay in tumor growth was observed when 1 x 10(5) units of IFN were administered at the site of tumor on days 1-4 after tumor challenge. Increasing the dose of IFN or extending therapy to 7 days did not afford any further inhibition of tumor growth. In vivo depletion of NK cells with anti-asialo monoganglioside antibody revealed that the delay in tumor growth was dependent on NK cells when IFN was given on days 1-4. Treatment for days 1-7, however, still inhibited tumor growth in the NK cell-depleted nude mice. In order to further ascertain the role of T-cells in IFN-induced tumor inhibition, T-cell reconstitution studies of nude mice were performed. Nude mice were reconstituted with 1 x 10(7), 2 x 10(7), and 5 x 10(7) T-cells on day -1 to tumor challenge and treated with IFN on days 1-7. The extent of the observed decrease of tumor sizes and tumor incidences among the T-cell-reconstituted groups was dependent on the dose of T-cells being administered in both IFN-treated and untreated animals. These data indicate that T-cells are essential for maintaining the growth-inhibitory effects of IFN. This is in contrast to NK cells whose role in IFN-induced inhibition of MSC tumor growth can be circumvented by increasing the dose of IFN.

Early lymphocyte recovery is a predictive factor for prolonged survival after autologous hematopoietic stem cell transplantation for acute myelogenous leukemia.

Absolute lymphocyte count (ALC) recovery correlates with survival after autologous hematopoietic stem cell transplantation (AHSCT) for patients with multiple myeloma, non-Hodgkin's lymphoma, and metastatic breast cancer. The role of ALC recovery in relationship to clinical outcome after AHSCT in patients with acute myelogenous leukemia is unknown. We analyzed 45 patients who underwent AHSCT at Mayo Clinic, Rochester, Minnesota between 1990 and 2000. The ALC threshold was selected at 500 cells/microl on day 15 post-AHSCT based on our previous studies. Thirty-two females and 13 males were included in the study with a median age of 45 years (range 12-75). The median follow-up was 14 months with a maximum of 129 months. The median overall and leukemia-free survival were significantly better for the 23 patients with ALC at day 15 > or =500 cells/microl compared with 22 patients with ALC <500 cells/microl (not yet reached vs 10 months, P < 0.0009; 105 vs 9 months, P < 0.0008, respectively). In conclusion, ALC > or =500 cells/microl on day 15 post-AHSCT is associated with better survival in acute myelogenous leukemia and requires further studies.

The dose of infused lymphocytes in the autograft directly correlates with clinical outcome after autologous peripheral blood hematopoietic stem cell transplantation in multiple myeloma.

Absolute lymphocyte count at day 15 (ALC-15) after autologous peripheral blood hematopoietic stem cell transplantation (APHSCT) is an independent prognostic factor for survival in multiple myeloma (MM); however, factors affecting ALC-15 in MM remain unknown. We hypothesized that the dose of infused peripheral blood autograft lymphocytes (autograft absolute lymphocyte count: A-ALC) impacts ALC-15 recovery. Between 1989 and 2001, 267 consecutive MM patients underwent APHSCT. We set out to determine the correlation between A-ALC and ALC-15 and the utility of A-ALC as a marker for ALC-15 recovery. A-ALC was found to be both a strong predictor for area under curve (AUC=0.93; P=0.0001) and strongly correlated with (r(s)=0.83; P=0.0001) ALC-15 recovery. Higher infused A-ALC was significantly correlated with an ALC-15>/=500/microl. In addition, median post-transplant overall survival (OS) and time to progression (TTP) were longer in patients who received an A-ALC>/=0.5 x 10(9) lymphocytes/kg versus A-ALC <0.5 x 10(9) lymphocytes/kg (58 vs 30 months, P=0.00022; 22 vs 15 months, P<0.00012, respectively). Multivariate analysis demonstrated A-ALC as an independent prognostic indicator for OS and TTP. These results indicate that an infused dose of autograft lymphocytes significantly impacts clinical outcome post-APHSCT in MM.

Aerosol granulocyte macrophage-colony stimulating factor: a low toxicity, lung-specific biological therapy in patients with lung metastases.

The objective was to study the feasibility of granulocyte macrophage-colony stimulating factor (GM-CSF) delivery to the lung using an aerosol in humans. A Phase I dose escalation study provided GM-CSF at three dose levels as a twice-a-day (BID) x 7 days schedule. Pulmonary functions were monitored using a remote spirometry device. Blood counts were checked at the beginning and end of each week of GM-CSF nebulization. If no toxicity was encountered, patients rested for 7 days and then were treated at the next dose level. Six of seven patients were successfully dose escalated from 60 microg/dose BID x 7 days, to 120 microg/dose BID x 7 days, then 240 microg/dose BID x 7 days. No toxicity was seen. Comparison of day 0 and day 7 blood leukocyte counts showed no significant increases in either leukocyte numbers or percentage of neutrophils. Pulmonary functions test changes were minor. No significant change in forced vital capacity, FEV1, peak flow, or FEF 25-75 related to either time or dose level was observed. One patient's lung metastases progressed. The other five patients received an additional 2-6 months of intermittent aerosol GM-CSF at dose level 3 without side effects. One patient with Ewing's sarcoma has a complete response, and a patient with melanoma had a partial response; the other three had stabilization of pulmonary metastases for 2-6 months. Aerosol delivery of GM-CSF is feasible, safe, and possibly effective. Aerosol cytokine delivery may achieve effective immunological activation against cancer in the lung and is worthy of further study.

Aerosol therapy for malignancy involving the lungs.

The lungs are common sites of involvement by primary and metastatic malignant disease. Patients with malignancies in the lung have limited treatment options and are usually not curable. Numerous investigators have studied the potential of delivering various therapeutic agents directly to the lungs and pulmonary lymphatics by nebulization. Most of the research involves the use of immunomodulatory strategies; a few aerosol studies of chemotherapy and gene therapy have also been conducted. Most of these studies have been conducted in animal models. A few human trials have also been completed. Results suggest that aerosol therapies have the potential to shrink pulmonary metastases of selected histologies, and that survival in selected patients with metastatic renal cell cancer may be prolonged. The approach to therapy of cancer in the lungs holds promise as a means to avoid systemic toxicity and obtain an improved therapeutic effect. Research is currently underway to address issues of local versus systemic toxicity, optimal drug delivery and selection of optimal drugs and schedules including outpatient aerosol therapy. Future issues in design of aerosol cancer treatment include identifying effective combinations of agents, schedules, and use of aerosol therapy at home as adjuvant therapy.

Respiratory syncytial virus pneumonitis-induced diffuse alveolar damage in an autologous bone marrow transplant recipient.

A 24-year-old woman with recurrent Hodgkin's lymphoma, stage IIB nodular sclerosing type, underwent an autologous bone marrow transplantation. Forty-five days after transplantation, an upper respiratory tract infection developed that progressed to respiratory distress necessitating mechanical ventilation. An open-lung biopsy demonstrated diffuse alveolar damage. After an extensive search for the cause of the respiratory compromise, we detected respiratory syncytial virus in a bronchoalveolar lavage specimen. The patient was immediately treated with aerosolized ribavirin and intravenous immunoglobulin; her symptoms resolved, and she was extubated 4 days after initiation of therapy.

Immune reconstitution after autologous hematopoietic stem cell transplantation.

Autologous hematopoietic stem cell transplantation has proved to be an effective treatment for certain hematologic malignancies. However, relapse rates are high during the first year after transplantation. These relapses are attributed to the failure of high-dose chemotherapy to eradicate minimal residual malignant disease. In allogeneic hematopoietic stem cell transplantation, the higher antitumor effects observed compared with those in autologous hematopoietic stem cell transplantation are based on the immunologically mediated graft-vs-tumor effect. Therefore, a better understanding of the mechanisms involved in immune reconstitution after hematopoietic stem cell transplantation may clarify the importance of various components of the recovery of the immune system as they pertain to eradication of residual tumor, as well as uncover possible interventions directed at maximizing this effect. This review focuses on immune reconstitution after autologous hematopoietic stem cell transplantation. Autologous hematopoietic stem cell transplantation is not affected by graft-vs-host disease or immunosuppressive therapy after transplantation to control graft-vs-host disease, providing a direct insight into the mechanisms involved in immune reconstitution after engraftment.

Prolonged survival associated with early lymphocyte recovery after autologous hematopoietic stem cell transplantation for patients with metastatic breast cancer.

Early absolute lymphocyte count (ALC) recovery at day 15 post-autologous stem cell transplantation (ASCT) is a powerful prognostic indicator for survival in multiple myeloma and non-Hodgkin's lymphoma. The relationship of ALC with clinical outcomes in metastatic breast cancer is unknown. We evaluated all 29 patients with metastatic breast cancer who underwent ASCT at the Mayo Clinic, Rochester, Minnesota, from 1994 to 1999. The ALC threshold was set at 500 cells/microl on day 15 post-ASCT based on previous experience with hematologic malignancies. All patients were followed for a minimum of 2 years or until death, with a median follow-up for living patients of 2.25 years. Of the 29 patients, 17 have died with disease progression, two are alive and have progressed, and 10 are alive without progression. The median overall and progression-free survival times were significantly better for the 20 patients with ALC > or = 500 cells/microl compared with the nine patients with ALC <500 cells/microl (not reached vs 14 months, P < 0.0001; 24 vs 7 months, P < 0.0015, respectively). In conclusion, ALC > or = 500 cells/microl on day 15 post-ASCT was associated with significantly better survival in patients with metastatic breast cancer, suggesting the importance of early immune recovery post-ASCT in these patients.

Immunomodulation of early engrafted natural killer cells with interleukin-2 and interferon-alpha in autologous stem cell transplantation.

High relapse rates during the first year after autologous stem cell transplantation (ASCT) for multiple myeloma or non-Hodgkin lymphoma are due to the failure of high-dose chemotherapy to eradicate minimal residual disease. Post-ASCT immunorecovery studies have shown that quantities of natural killer (NK) cells return to normal within 1 month post-ASCT in contrast to the recovery of T and B cell populations (up to 1 year). Preclinical studies have demonstrated that NK cells have potent antitumor activity. IL-2 and IFN-alpha enhance NK-cell activity. We investigated the efficacy of IL-2 and IFN-alpha to up-regulate NK-cell cytotoxicity at 14 days post ASCT. Twenty patients undergoing ASCT had PBMCs collected pretransplantation and at 14 days post transplantation. PBMCs (effector cells) from each blood sample were incubated in vitro with IFN-alpha and IL-2 at 10000 IU/ml. NK cell activity was determined by sodium chromate (51)Cr release assay for lysis of K562 target cells. IL-2 and IFN-alpha each increased lysis of K562 cells compared with placebo (effector-to-target ratio, 50:1, P < 0.001). Increased NK cell activity occurred in samples from all patients. IL-2 and IFN-alpha up-regulated NK cell activity at 14 days post ASCT. They may be useful as immunomodulators as early as 14 days post ASCT to eradicate or control minimal residual disease.