Cancer Treatment

Donor lymphocyte infusion

DLI is well studied in chronic myelogenous leukemia but less so in other hematological conditions.

DLI induces complete remissions in the majority of patients with chronic myeloid leukemia (CML) in early-stage relapse and in less than 30% of patients with relapsed acute leukemia, myelodysplasia, and multiple myeloma. DLI-induced remissions of chronic phase CML are durable, but as many as half of patients with other diseases ultimately relapse. Complications of DLI include acute and chronic graft-vs-host disease (GVHD) and aplasia, which induce profound immunosuppression and susceptibility to opportunistic infections. There is a strong correlation of GVHD and disease response.
Other hematologic malignancies do not respond to DLI as well as early-stage CM. In general, less than 30% of patients with relapsed acute leukemia,myelodysplasia, and multiple myeloma achieve complete responses to DLI. As many close to half or more of patients who do achieve a complete response may be expected to relapse after DLI. DLI has been researched as a treatment for a variety of hematologic malignancies, including most prominently chronic myeloid leukemia, but also acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, myelodysplastic syndromes, chronic lymphocytic leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma. Studies are limited due to small numbers but they have provided evidence that DLI can establish a graft-versus-leukemia/lymphoma effect. Whetehr a second DLI adds something to GVHD is not known.

While DLI-induced remissions are achieved in only a small number of AML patients, many of these remissions may be durable. Of 10 patients in the North American registry who had achieved a complete remission (CR) from DLI, only two subsequently relapsed at 1–3 years. At a median follow-up of 1 year, five patients were alive and in CR. The two that relapsed died of disease and three other patients had died of treatment-related causes.

The effects of DLI appear to be similar in patients receiving unrelated donor transplants, although only small numbers of recipients of unrelated DLI (UDLI) have been reported. In collaboration with the National Marrow Donor Program, we retrospectively identified 23 AML patients who received UDLI for relapsed AML.5 The median follow-up was 10 weeks (range 4–102 weeks). Of the patients evaluable for response to DLI alone, 42% achieved a CR. However, only 4/23 of all patients (17%) had a durable CR. From this study and others, it is clear that the most significant predictor of survival and disease-free survival (DFS) was the time from transplant to relapse. Of interest, there was no dose–response effect identified in the unrelated donor setting though the majority of patients received more than 1  107 mononuclear cells/kg. This might argue agains a second DLI.

Unfortunately, not only response to DLI in AML is disappointing, but also the toxicity is significant. Up to 30% of patients will develop grade III–IV acute GVHD, and treatment-related mortality rates are estimated to be up to 20%.

Porter D, Collins R, Hardy C, Kernan N, Drobyski W, Giralt S et al. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood 2000; 95: 1214–1221.

Leis J, Porter D. Unrelated donor leukocyte infusions to treat relapse after unrelated donor bone marrow transplantation. Leukemia Lymphoma 2002; 43: 9–17.

Levine J, Braun T, Penza S, Beatty P, Cornetta K, Martino R et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem cell transplantation. J Clin Oncol 2001; 20: 405–412.

Christoph Schmid, Myriam Labopin, Arnon Nagler, Martin Bornhäuser, Jürgen Finke, Athanasios Fassas, Liisa Volin, Günham Gürman, Johan Maertens, Pierre Bordigoni, Ernst Holler, Gerhard Ehninger, Emmanuelle Polge, Norbert-Claude Gorin, Hans-Jochem Kolb, Vanderson Rocha Donor Lymphocyte Infusion in the Treatment of First Hematological Relapse After Allogeneic Stem-Cell Transplantation in Adults With Acute Myeloid Leukemia: A Retrospective Risk Factors Analysis and Comparison With Other Strategies by the EBMT Acute Leukemia Working Party Journal of Clinical Oncology, Vol 25, No 31 (November 1), 2007: pp. 4938-4945

Donor Lymphocyte Infusion after Allogeneic Stem Cell Transplantation
ASCO Educational Book, January 1, 2008; 2008(1): 334 - 337.

Decitabine for acute myelogenous leukemia

Dacogen (decitabine) is DNA methyltransferase inhibitors (DMTI) approved by the FDA for use in all French- American British (FAB) categories for MDS. The response rates for Dacogen were 30% (9% CR, 8% PR, 13% HI). Median TTP was prolonged from 7.8 months to 12.1 months compared to supportive care (p=0.1). Higher response rates have been reported in a single institution trial using lower doses of Dacogen. This drug is FDA approved for AML.

For acute meulogenous leukemia, less is known. A 2007 review, looked at 33 patients.  with the WHO criteria of AML that were treated with decitabine alone (23 patients) or in combination with valproic acid (10 patients) as first-line therapy. There were 20 men (61%) and their median age was 72, range 39 to 85. Median bone marrow blasts at study entry was 26%, and 14 (42%) had >30% blasts. There were three different schedules of decitabine IV, which gave a total of 100–150 mg/m2/course over 3–10 days. Of the 33 patients treated, there were 8 CRs (24%) and 9 marrow CR/PR/Hematologic improvement (27%) for a total response rate of 17 (52%). Overall mortality at 4 weeks and 8 weeks was 3% and 15%, respectively. At a median follow-up of 20 months, median survival of the entire group was 12.6 months (95% CI: 6.5–23.0), and 2-year survival was 25% (95% CI: 13–48), which compares favorably to reported AML survival in this age group in the United States. The study concluded that decitabine is an effective and less toxic treatment in this AML age group and may prolong survival compared with supportive care.

A phase II study, NCT00349596, is looking at this drug in a phase II setting. The goal of this clinical research study is to find the safety of decitabine in patients with acute lymphocytic leukemia.

Silverman L, Demakos E, Peterson B, et L. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J. Clin. Oncol 2002; 10: 2241-2252.

Saba H, Rosenfeld C, Issa JP, et al. First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome. American Society of Hematology Meeting. San Diego, Calif. 2004. Abstract #64.

Kantarjian H, O'Brien S, Giles F, et al.Decitabine Low-Dose Schedule (100 mg/m2/Course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract #2522.

Donor lymphocyte infusion to treat chimerism

The donor cell reinfusion in this case is not being used to provide new graft versus leukemia effect but to destroy remaining normal patient cells and to provide engraftment. It ahs been observed that chimerism is risk factor for relapse of the leukemia. The status of DLI to treat disase is still unsettled and the use of DLI to decrease chimerism is even less established. There would have been no objection to a reinfusion of stem cells to re-engraft which I would see as a continuation of the previously approved stem cell transplant. However, using DLI in this fashion is experimental since the contention that it does os is supported by case reports and series only

Because of the large number of acute leukemia patients who relapse after alloBMT, there has been a substantial experience in the treatment of these patients with DLI. Using median doses of >/=108 T cells/kg, DLI alone induces complete remissions in 8% of patients with ALL and 22% of patients with acute myeloid leukemia (AML). When patients who receive chemotherapy prior to DLI are included, complete response rates are significantly higher, ranging from 33% to 37%. However, follow- up of ALL patients reveals few, if any, long-term survivors, although 1 has been reported. Relapse occurs in approximately one quarter to one half of patients with AML in remission after DLI, leaving a long-term survival rate of approximately 10% to 15%.

DLI has been researched as a treatment for a variety of hematologic malignancies, including most prominently chronic myeloid leukemia, but also acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, myelodysplastic syndromes, chronic lymphocytic leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma. Studies are limited due to small numbers but they have provided evidence that DLI can establish a graft-versus-leukemia/lymphoma effect.

Fewer patients with relapsed myelodysplasia have been treated with DLI. However, because myelodysplasia progresses more slowly than AML, the rate of complete remissions may be higher. The natural history of myelodysplasia patients who enter into a remission following DLI has not been described.

It is not clear whether administration of induction chemotherapy at the time of relapse improves long-term survival following DLI. It is usually thought that it does but without a strong conifrmation in the literature. A randomized trial with analysis performed on an intent-to-treat basis is needed to answer this question.

Litzow, Mark R Progress and strategies for patients with relapsed and refractory acute myeloid leukemia. Current Opinion in Hematology. 14(2):130-137, March 2007.

Luznik L, Fuchs EJ. Donor lymphocyte infusions to treat hematologic malignancies in relapse after allogeneic blood or marrow transplantation.Cancer Control. 2002 Mar-Apr;9(2):123-37.

Ishikawa J, Maeda T, Kashiwagi H, et al. Successful second allogeneic peripheral blood stem cell transplantation and donor leukocyte infusion in patients with relapsed acute leukemia using the same donor as for the initial allogeneic bone marrow transplantation. Bone Marrow Transplantation. 2003; 31:1057-1059.

Levine JE, Braun T, Penza SL, et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem cell transplantation. J Clin Oncol. 2002; 20(2):405-412.

E . Orsini , E . Alyea , A . Chillemi , R . Schlossman , S . McLaughlin , C . Canning , R . Soiffer , K . Anderson , J . Ritz Conversion to full donor chimerism following donor lymphocyte infusion is associated with disease response in patients with multiple myeloma . 
Biology of Blood and Marrow Transplantation , Volume 6 , Issue 4 , Pages 375 - 386, 2000

Suradej Hongeng et al, Donor Lymphocyte Infusion Can Eliminate Mixed Chimerism in Nonmyeloablative Stem Cell Transplantation for Correction of Hyper-IgM Syndrome Acta Hematologica Vol. 114, No. 3, 2005

Length of stay for acute myelocytic leukemia

Standard therapy of of acute myelogenous leukemia (excluding acute promyelocytic leukemia).
Induction therapy: Various acceptable induction regimens are available. The most common approach is called ”3 and 7,” which consists of 3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone), combined with 100 mg/m2 of arabinosylcytosine (araC) as a 24-hour infusion daily for 7 days. Idarubicin is given at a dose of 12 mg/m2/d for 3 days, daunorubicin at 45-60 mg/m2/d for 3 days, or mitoxantrone at 12 mg/m2/d for 3 days. Using these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% enter remission following a second course of therapy. Alternatively, high-dose araC combined with idarubicin, daunorubicin, or mitoxantrone can be used as induction therapy in younger patients. The use of high-dose araC outside the setting of a clinical trial is considered controversial.

The usual length of stay incorporates the days for infusion as well as to treat the sequellae of tehrapy that begin to onset at about a week later. These include pancytopenia, bleeding, infection and others. For this reason it is standard to continue inpatient care and to also isolate these patietns tp prevent infection, until hematologic recovery. Recovery takes at least 2 weeks and longer, if remission has not been achieved and the patient receives a second induction. Average length of stay for acute myelocytic leukemia ranges between 17 and 25 days in the USA.

There are major centers that have experimented with outpatient care in a nearby hotel facility but this requires a specialized program and is not routine.

Estey EH. Therapeutic options for acute myelogenous leukemia.Cancer. 2001 Sep 1;92(5):1059-73.

nccn.org, AML

Length of stay for acute myelocytic leukemia

Standard therapy of of acute myelogenous leukemia (excluding acute promyelocytic leukemia).
Induction therapy: Various acceptable induction regimens are available. The most common approach is called ”3 and 7,” which consists of 3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone), combined with 100 mg/m2 of arabinosylcytosine (araC) as a 24-hour infusion daily for 7 days. Idarubicin is given at a dose of 12 mg/m2/d for 3 days, daunorubicin at 45-60 mg/m2/d for 3 days, or mitoxantrone at 12 mg/m2/d for 3 days. Using these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% enter remission following a second course of therapy. Alternatively, high-dose araC combined with idarubicin, daunorubicin, or mitoxantrone can be used as induction therapy in younger patients. The use of high-dose araC outside the setting of a clinical trial is considered controversial.

The usual length of stay incorporates the days for infusion as well as to treat the sequellae of tehrapy that begin to onset at about a week later. These include pancytopenia, bleeding, infection and others. For this reason it is standard to continue inpatient care and to also isolate these patietns tp prevent infection, until hematologic recovery. Recovery takes at least 2 weeks and longer, if remission has not been achieved and the patient receives a second induction. Average length of stay for acute myelocytic leukemia ranges between 17 and 25 days in the USA.

Treating biphenotypic leukemia

A minority of acute leukemias have features characteristic of both the myeloid and lymphoid lineages and for this reason are designated mixed-lineage, hybrid or biphenotypic acute leukemias (BAL). There have been difficulties in establishing whether BAL represents a distinct clinico-biological entity due to a lack of objective criteria for distinguishing BAL from acute myeloid leukemias (AML) or acute lymphoblastic leukemias (ALL) with aberrant expression of a marker from another lineage. As such, it is often treated as AML but with some component of treatment being taken from acute lymphocytic leukemia regimens.There is no agreement on how the disease should be treated. The majority of patients receive treatment according to the morphology of the blasts, with either AML or ALL induction. Cytogenetic abnormalities are observed in a high percentage of bilineal and biphenotypic leukemias. Approximately 33% of cases have the Philadelphia chromosome, and some cases are associated with t(4;11)(q21;q23) or other 11q23 abnormalities. Gleevec can be added in such cases.

Brunning RD, Matutes E, Harris NL, et al.: Acute myeloid leukaemia: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 77-80.

Aribi, Ahmedet al, Acute leukaemia: a case series.British Journal of Haematology. 138(2):213-216, July 2007.

Vidaza and Myelotarg for acute meylogenous leukemia

On May 19, 2004 the U.S. Food and Drug Administration approved azacitidine as injectable suspension (Vidaza) for treatment of patients with the following MDS subtypes: RA or RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), RAEB, RAEB-T, and CMML. Azacitidine is the first agent approved for treatment of myelodysplastic syndrome. It is now in trials for acute meyelogenous leukemia - AML.

Gemtuzumab ozogamicin (GO) (Mylotarg, CMA-676) is a novel chemotherapeutic agent consisting of an anti-CD33 monoclonal antibody linked to calicheamicin, and is associated with a 30% response rate in patients with CD33-positive acute myeloid leukemia (AML) in first relapse.

A pilot study ot these two drugs for the elderly in combination is ongoing at Loyola University Medical School. It is clearly investigational.

The role of flow cytometry in diagnosis of acute leukemia

Acute leukemia displays characteristic patterns of surface antigen expression (CD antigens), which facilitate their identification and proper classification and hence play an important role in instituting proper treatment plans. In addition to enzyme cytochemical analysis, multiparameter flow cytometric analysis has become commonplace in most laboratories for that purpose. Aside from identification of blasts, flow cytometry is especially useful in the correct identification of AML MO, differentiation of APL from AML M1/M2, and correct identification of TdT-negative ALL and unusual variants, such as transitional B-cell ALL and undifferentiated and biphenotypic acute leukemias. Distinction between lymphoid and myeloid leukemias, most often made by flow cytometry, is crucially important. Several advances in flow cytometry, including availability of new monoclonal antibodies, improved gating strategies, and multiparameter analytic techniques, have all dramatically improved the utility of flow cytometry in the diagnosis and classification of leukemia.

Flow cytometery is very helpful in a diagnosis of any leukemic condition but is most useful for differentiating different leukemia subtypes. Final diagnosis should never relay on one report alone but should be produced by a consideration of clinical findings and history, examination of the peripheral smear and bone marrow morphology, and, if necessary special stains. Flow cytometery represents one of several sources of information that go into making a secure diagnosis. It should not be relied on in isolation to make a diagnosis.

Does the flow cytometry report give a positive diagnosis of Acute Monoblastic Leukemia?
This report is a strong support to this diagnosis but cannot be used exclusively.

Kaleem, Zahid,  Crawford, Eric, Flow cytometric analysis of acute leukemias: Diagnostic utility and critical analysis of data Arch Pathol Lab Med. 2003;127:42-48

Kaleem Z, Crawford E, Pathan MH, Jasper L, Covinsky MA, Johnson LR, White G.
Flow cytometric analysis of acute leukemias. Diagnostic utility and critical analysis of data.Arch Pathol Lab Med. 2003 Jan;127(1):42-8.

Stem Cell Transplant for relapsed acute myelogenous leukemia

Refractory and relapsed disease occurs in most acute myelogenous leukemia patients. Salvage chemotherapy offers a 30–70% chance of a second complete remission. Unfortunately, this second remission is usually short lived and salvage chemotherapy is rarely curative. Allogeneic bone marrow transplant, either human leukocyte antigen (HLA)-sibling matched or matched unrelated donor, is the only treatment to offer long-term disease-free survival and possible cure.  Allogeneic transplantation is standard of care after AML relapse.

Estey EH. Therapeutic options for acute myelogenous leukemia.Cancer. 2001 Sep 1;92(5):1059-73.

nccn.org, AML

Socie G. Current issues in allogeneic stem cell transplantation. Hematology. Sep-Oct 2005;10 Suppl 1:63.

Granulocute Transfusions

Lay Summary: An ssessment of the role of granulocyte transfusions in 2008.

Granulocyte transfusions are requested by clinicians for use in patients with refractory infection or at high risk of developing severe infection (Strauss 2003). Most patients prescribed granulocyte transfusions are those with cancer related neutropenia, who are receiving myeloablative chemotherapy with or without haemopoietic stem cell rescue. Interest in the use of granulocytes remains high (Van Burik & Weisdorf, 2002; Price 2006), and requests for granulocyte components for transfusion have steadily increased in England and Wales during the last five years. This has been driven by publications describing transfusion in neutropenic patients both for therapeutic indications, when they have an infection refractory to antimicrobials (Hubel et al. 2002) and for secondary prophylaxis, in patients who have had severe bacterial or fungal infections previously but who require a further cycle of chemotherapy or haemopoietic stem cell rescue (Kerr et al. 2003, Oza et al., 2006). Recent studies with promising but overall inconclusive results have been reported both in adults (Oza et al., 2006) and children (Sachs et al., 2006).

The exact clinical role for granulocyte transfusions (whether derived from whole blood or collected by apheresis) therefore remains unclear. Potential efficacy including a dose dependent effect has been raised by systematic reviews/meta-analyses (Vamvakas et al. 1996; Vamvakas et al. 1997; Stanworth et al., 2004), and in animal studies. The existing literature is, perhaps not surprisingly, otherwise heavily dominated by case reports and small case series, with the significant attendant risk of publication bias. However, it should be acknowledged that anecdotal evidence of benefit in selected patients from physicians in the UK and abroad can be found, and that a number of very recent publications have again pointed to evidence of benefit, including one study based on biological randomisation - although this study was underpowered to detect an effect on mortality (Oza et al., 2006).