If a patient is resistant to either cladribine or pentostatin, then second-line therapy is pursued.

Monoclonal antibodies The most common treatment for cladribine-resistant disease is infusing monoclonal antibodies that destroy cancerous B cells. Rituximab is by far the most commonly used. Most patients receive one IV infusion over several hours each week for four to eight weeks. A 2003 publication found two partial and ten complete responses out of 15 patients with relapsed disease, for a total of 80% responding. The median patient (including non-responders) did not require further treatment for more than three years. This eight-dose study had a higher response rate than a four-dose study at Scripps, which achieved only 25% response rate. Rituximab has successfully induced a complete response in Hairy Cell-Variant.

Rituximab's major side effect is serum sickness, commonly described as an "allergic reaction", which can be severe, especially on the first infusion. Serum sickness is primarily caused by the antibodies clumping during infusion and triggering the complement cascade. Although most patients find that side effects are adequately controlled by anti-allergy drugs, some severe, and even fatal, reactions have occurred. Consequently, the first dose is always given in a hospital setting, although subsequent infusions may be given in a physician's office. Remissions are usually shorter than with the preferred first-line drugs, but hematologic remissions of several years' duration are not uncommon.

Other B cell-destroying monoclonal antibodies such as Alemtuzumab, Ibritumomab tiuxetan and I-131 Tositumomab may be considered for refractory cases.

Interferon-alpha Interferon-alpha is an immune system hormone that is very helpful to a relatively small number of patients, and somewhat helpful to most patients. In about 65% of patients, the drug helps stabilize the disease or produce a slow, minor improvement for a partial response.

The typical dosing schedule injects at least 3 million units of Interferon-alpha (not pegylated versions) three times a week, although the original protocol began with six months of daily injections.

Some patients tolerate IFN-alpha very well after the first couple of weeks, while others find that its characteristic flu-like symptoms persist. About 10% of patients develop a level of depression. It is possible that, by maintaining a steadier level of the hormone in the body, that daily injections might cause fewer side effects in selected patients. Drinking at least two liters of water each day, while avoiding caffeine and alcohol, can reduce many of the side effects.

A drop in blood counts is usually seen during the first one to two months of treatment. Most patients find that their blood counts get worse for a few weeks immediately after starting treatment, although some patients find their blood counts begin to improve within just two weeks.

It typically takes six months to figure out whether this therapy is useful. Common criteria for treatment success include:

- normalization of hemoglobin levels (above 12.0 g/dL),

- a normal or somewhat low platelet count (above 100 K/µL), and

- a normal or somewhat low absolute neutrophil count (above 1.5 K/µL).

If it is well tolerated, patients usually take the hormone for 12 to 18 months. An attempt may be made then to end the treatment, but most patients discover that they need to continue taking the drug for it to be successful. These patients often continue taking this drug indefinitely, until either the disease becomes resistant to this hormone, or the body produces an immune system response that limits the drug's ability to function. A few patients are able to achieve a sustained clinical remission after taking this drug for six months to one year. This may be more likely when IFN-alpha has been initiated shortly after another therapy. Interferon-alpha is considered the drug of choice for pregnant women with active HCL, although it carries some risks, such as the potential for decreased blood flow to the placenta.

Interferon-alpha works by sensitizing the hairy cells to the killing effect of the immune system hormone TNF-alpha, whose production it promotes. IFN-alpha works best on classic hairy cells that are not protectively adhered to vitronectin or fibronectin, which suggests that patients who encounter less fibrous tissue in their bone marrow biopsies may be more likely to respond to Interferon-alpha therapy. It also explains why non-adhered hairy cells, such as those in the bloodstream, disappear during IFN-alpha treatment well before reductions are seen in adhered hairy cells, such as those in the bone marrow and spleen.

Splenectomy can produce long-term remissions in patients whose spleens seem to be heavily involved, but its success rate is noticeably lower than cladribine or pentostatin. Splenectomies are also performed for patients whose persistently enlarged spleens cause significant discomfort or in patients whose persistently low platelet counts suggest Idiopathic thrombocytopenic purpura.

Bone marrow transplants are usually shunned in this highly treatable disease because of the inherent risks in the procedure. They may be considered for refractory cases in younger, otherwise healthy individuals. "Mini-transplants" are possible.

People with anemia or thrombocytopenia may also receive red blood cells and platelets through blood transfusions. Blood transfusions are always irradiated to remove white blood cells and thereby reduce the risk of graft-versus-host disease. Patients may also receive a hormone to stimulate production of red blood cells. These treatments may be medically necessary, but do not kill the hairy cells.

People with low neutrophil counts may be given filgrastim or a similar hormone to stimulate production of white blood cells. However, a 1999 study indicates that routine administration of this expensive injected drug has no practical value for HCL patients after cladribine administration. In this study, patients who received filgrastim were just as likely to experience a high fever and to be admitted to the hospital as those who did not, even though the drug artificially inflated their white blood cell counts. This study leaves open the possibility that filgrastim may still be appropriate for patients who have symptoms of infection, or at times other than shortly after cladribine treatment.

Although hairy cells are technically long-lived, instead of rapidly dividing, some late-stage patients are treated with broad-spectrum chemotherapy agents such as methotrexate that are effective at killing rapidly dividing cells. This is not typically attempted unless all other options have been exhausted and it is typically unsuccessful.

While investigational drug therapies exist, no curative drug treatment exists for any of the MPDs. The goal of treatment for ET and PV is prevention of thrombohemorrhagic complications. The goal of treatment for MF is amelioration of anemia, splenomegaly, and other symptoms. Low-dose aspirin is effective in PV and ET. Tyrosine kinase inhibitors like imatinib have improved the prognosis of CML patients to near-normal life expectancy.

Recently, a "JAK2" inhibitor, namely ruxolitinib, has been approved for use in primary myelofibrosis. Trials of these inhibitors are in progress for the treatment of the other myeloproliferative neoplasms.

Targeted therapy attacks cancer cells at a specific target, with the aim of not harming normal cells.

- Alemtuzumab is a mAb directed against CD52 used in CLL.

- Rituximab, ofatumumab, and obinutuzumab are antibodies against CD20 used to treat CLL.

- Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is used to treat CLL.

- Idelalisib is a PI3K inhibitor. and is taken orally.

- Venetoclax is a Bcl-2 inhibitor used to treat people with CLL who have 17p deletion (deletion located on the chromosome 17 short arm) and who have been treated with at least one prior therapy.

Most patients with T-cell prolymphocytic leukemia require immediate treatment.

T-cell prolymphocytic leukemia is difficult to treat, and it does not respond to most available chemotherapeutic drugs. Many different treatments have been attempted, with limited success in certain patients: purine analogues (pentostatin, fludarabine, cladribine), chlorambucil, and various forms of combination chemotherapy regimens, including cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), etoposide, bleomycin (VAPEC-B).

Alemtuzumab (Campath), an anti-CD52 monoclonal antibody that attacks white blood cells, has been used in treatment with greater success than previous options. In one study of previously treated people with T-PLL, people who had a complete response to alemtuzumab survived a median of 16 months after treatment.

Some patients who successfully respond to treatment also undergo stem cell transplantation to consolidate the response.

To overcome imatinib resistance and to increase responsiveness to TK inhibitors, four novel agents were later developed. The first, dasatinib, blocks several further oncogenic proteins, in addition to more potent inhibition of the BCR-ABL protein, and was initially approved in 2007 by the US FDA to treat CML in patients who were either resistant to or intolerant of imatinib. A second new TK inhibitor, nilotinib, was also approved by the FDA for the same indication. In 2010, nilotinib and dasatinib were also approved for first-line therapy, making three drugs in this class available for treatment of newly diagnosed CML. In 2012, Radotinib joined the class of novel agents in the inhibition of the BCR-ABL protein and was approved in South Korea for patients resistant to or intolerant of imatinib. Bosutinib received US FDA and EU European Medicines Agency approval on September 4, 2012 and 27 March 2013 respectively for the treatment of adult patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.

Radiation to the spleen does not generally result in a decrease in spleen size or reduction of platelet transfusion requirement.

The role of chemotherapy or other pharmacologic treatments against JMML before bone marrow transplant has not been studied completely and its importance is still unknown. Chemotherapy by itself has proven unable to bring about long-term survival in JMML.

- Low-dose conventional chemotherapy: Studies have shown no influence from low-dose conventional chemotherapy on JMML patients’ length of survival. Some combinations of 6-mercaptopurine with other chemotherapy drugs have produced results such as decrease in organ size and increase or normalization of platelet and leukocyte count.

- Intensive chemotherapy: Complete remission with ongoing durability from JMML has not been possible through use of intensive chemotherapy, but it is still used at times because it has improved the condition of a small but significant number of JMML patients who do not display an aggressive disease. The COG JMML study administers 2 cycles of fludarabine and cytarabine for 5 consecutive days along with 13-cis retinoic acid during and afterwards. The EWOG-MDS JMML study, however, does not recommend intensive chemotherapy before bone marrow transplant.

- 13-cis retinoic acid (Isotretinoin): In the lab, 13-cis-retinoic acid has inhibited the growth of JMML cells. The COG JMML study therefore includes 13-cis-retinoic acid in its treatment protocol, though its therapeutic value for JMML remains controversial.

Autologous stem cell transplantation, using the recipient's own cells, is not curative. Younger individuals, if at high risk for dying from CLL, may consider allogeneic hematopoietic stem cell transplantation (HSCT). Myeloablative (bone marrow killing) forms of allogeneic stem cell transplantation, a high-risk treatment using blood cells from a healthy donor, may be curative, but treatment-related toxicity is significant. An intermediate level, called reduced-intensity conditioning allogeneic stem cell transplantation, may be better tolerated by older or frail patients.

In the past, antimetabolites (e.g., cytarabine, hydroxyurea), alkylating agents, interferon alfa 2b, and steroids were used as treatments of CML in the chronic phase, but since the 2000s have been replaced by Bcr-Abl tyrosine-kinase inhibitors drugs that specifically target BCR-ABL, the constitutively activated tyrosine kinase fusion protein caused by the Philadelphia chromosome translocation. Despite the move to replacing cytotoxic antineoplastics (standard anticancer drugs) with tyrosine kinase inhibitors sometimes hydroxyurea is still used to counteract the high leukocyte counts encountered during treatment with tyrosine kinase inhibitors like imatinib; in these situations it may be the preferred myelosuppressive agent due to its relative lack of leukemogenic effects and hence the relative lack of potential for secondary hematologic malignancies to result from treatment. IRIS, an international study that compared interferon/cytarabine combination and the first of these new drugs imatinib, with long-term follow up, demonstrated the clear superiority of tyrosine-kinase-targeted inhibition over existing treatments.

Alemtuzumab has been investigated for use in treatment of refractory T-cell large granular lymphocytic leukemia.

Natural killer (NK) cell therapy is used in pediatrics for children with relapsed lymphoid leukemia. These patients normally have a resistance to chemotherapy, therefore, in order to continue on, must receive some kind of therapy. In some cases, NK cell therapy is a choice.

NK cells are known for their ability to eradicate tumor cells without any prior sensitization to them. One problem when using NK cells in order to fight off lymphoid leukemia is the fact that it is hard to amount enough of them to be effective. One can receive donations of NK cells from parents or relatives through bone marrow transplants. There are also the issues of cost, purity and safety. Unfortunately, there is always the possibility of Graft vs host disease while transplanting bone marrow.

NK cell therapy is a possible treatment for many different cancers such as Malignant glioma.

Many different anti-cancer drugs are effective for the treatment of AML. Treatments vary somewhat according to the age of the patient and according to the specific subtype of AML. Overall, the strategy is to control bone marrow and systemic (whole-body) disease, while offering specific treatment for the central nervous system (CNS), if involved.

In general, most oncologists rely on combinations of drugs for the initial, "induction phase" of chemotherapy. Such combination chemotherapy usually offers the benefits of early remission and a lower risk of disease resistance. "Consolidation" and "maintenance" treatments are intended to prevent disease recurrence. Consolidation treatment often entails a repetition of induction chemotherapy or the intensification chemotherapy with additional drugs. By contrast, maintenance treatment involves drug doses that are lower than those administered during the induction phase.

The treatment a child will undergo is based on the child's age, overall health, medical history, their tolerance for certain medications, procedures, and therapies, along with the parents' opinion and preference.

- Chemotherapy is a treatment that uses drugs to interfere with the cancer cells ability to grow and reproduce. Chemotherapy can be used alone or in combination with other therapies. Chemotherapy can be given either as a pill to swallow orally, an injection into the fat or muscle, through an IV directly into the bloodstream, or directly into the spinal column.

- A stem cell transplant is a process by which healthy cells are infused into the body. A stem-cell transplant can help the human body make enough healthy white blood cells, red blood cells, or platelets, and reduce the risk of life-threatening infections, anemia, and bleeding. It is also known as a bone-marrow transplant or an umbilical-cord blood transplant, depending on the source of the stem cells. Stem cell transplants can use the cells from the same person, called an autologous stem cell transplant or they can use stem cells from other people, known as an allogenic stem cell transplant. In some cases, the parents of a child with childhood leukemia may conceive a saviour sibling by preimplantation genetic diagnosis to be an appropriate match for the HLA antigen.

There are many possible treatments for CML, but the standard of care for newly diagnosed patients is imatinib (Gleevec) therapy. Compared to most anti-cancer drugs, it has relatively few side effects and can be taken orally at home. With this drug, more than 90% of patients will be able to keep the disease in check for at least five years, so that CML becomes a chronic, manageable condition.

In a more advanced, uncontrolled state, when the patient cannot tolerate imatinib, or if the patient wishes to attempt a permanent cure, then an allogeneic bone marrow transplantation may be performed. This procedure involves high-dose chemotherapy and radiation followed by infusion of bone marrow from a compatible donor. Approximately 30% of patients die from this procedure.

Immunoglobulin E (IgE) is important in mast cell function. Immunotherapy with anti-IgE immunoglobulin raised in sheep resulted in a transient decrease in the numbers of circulating mast cells in one patient with mast cell leukemia. Although splenectomy has led to brief responses in patients with mast cell leukemia, no firm conclusions as to the efficacy of this treatment are possible. Chemotherapy with combination of cytosine arabinoside and either idarubicin, daunomycin, or mitoxantrone as for acute myeloid leukemia has been used. Stem cell transplantation is an option, although no experience exists concerning responses and outcome.

Generally, acute myeloid leukemia is treated using chemotherapy consisting of an induction phase and consolidation phase (Dohner et al., 2009). Patients may also consider hematopoietic stem cell transplantation as a second mode of tackling the cancer. The most novel research is being done in tyrosine kinase inhibitors; however M2 acute myeloid leukemia treatment research involves molecules that inhibit the fusion oncoprotein AML1-ETO. Therefore, in terms of M2 subtype acute myeloid leukemia, the most prominent target is the abnormal AML1-ETO fusion protein. Similarly, chronic myeloid leukemia (CML) is comparable to acute myeloid leukemia M2 because it also forms a fusion oncoprotein – BCR-Abl. The developed tyrosine kinase inhibitor, imatinib mesylate, has had a tremendous effect on stopping cancer progression in the majority of chronic myeloid leukemia patients. BCR-Abl is constitutively active due chromosome translocation; therefore it over-phosphorylates the tyrosine kinase. Imatinib mesylate works to block BCR-Abl’s activity by blocking the active kinase domain (Fava et al., 2011).

Celastrol is a compound extracted from Tripterygium wilfordii that has anti-cancer properties. It was found to inhibit cell proliferation through the down regulation of AML1-ETO fusion oncoprotein. Celastrol inhibits the fusion oncoprotein by inducing mitochondrial instability and initiating caspase activity The decrease of AML1-ETO also results in lower levels of C-KIT kinases, Akt/PKB, STAT3, and Erk1/2 – all of which are involved in cell signaling and gene transcription (Yu et al., 2016).

Histone deacetylase inhibitors such as valproic acid (VPA), vorinostat, and all-trans retinoic acid (ATRA) are effective in targeting acute myeloid leukemia with the AML1-ETO fusion protein. The HDAC inhibitors are known to induce apoptosis through accumulation of DNA damage, inhibition of DNA repair, and activation of caspases. These inhibitors are extra sensitive to the fusion proteins. Vorinostat has been proven to cause a greater accumulation of DNA damage in fusion protein expressing cells and is directly correlated with the reduction of DNA repair enzymes (Garcia et al., 2008). Romidepsin, a drug in phase two clinical trials, has demonstrated higher efficacy in patients with AML1-ETO fusion protein leukemia (Odenike et al., 2008). Although many clinical evaluations have proven HDAC inhibitors have a promising effect on M2 subtype acute myeloid leukemia, it has not been approved as an official treatment.

In t(6;9) acute myeloid leukemia, FLT3-ITD and the DEK-NUP214 protein are potential targets for treatment. Sorafenib is a kinase inhibitor used as a treatment for kidney and liver cancer. The kinase inhibitor blocks serine-threonine kinase RAF-1 as well as FLT-ITD (Kindler, 2010). The drug has been proven to be effective in reducing FLT3-ITD overexpression (Metzelder et al., 2009). In patients with DEK-NUP214, it was found that the fusion oncoprotein caused an upregulation of mTORC1 (Sanden et al., 2013). Thus, a mTORC inhibitor could be a potential treatment.

Treatment primarily consists of reducing eosinophil levels and preventing further damage to organs. Corticosteroids, such as Prednisone, are good for reducing eosinophil levels and antineoplastics are useful for slowing eosinophil production. Surgical therapy is rarely utilised, however splenectomy can reduce the pain due to spleen enlargement. If damage to the heart (in particular the valves), then prosthetic valves can replace the current organic ones. Follow-up care is vital for the survival of the patient, as such the patient should be checked for any signs of deterioration regularly. After promising results in drug trials (95% efficiency in reducing blood eosinophil count to acceptable levels) it is hoped that in the future hypereosinophilic syndrome, and diseases related to eosinophils such as asthma and eosinophilic granulomatosis with polyangiitis, may be treated with the monoclonal antibody Mepolizumab currently being developed to treat the disease. If this becomes successful, it may be possible for corticosteroids to be eradicated and thus reduce the amount of side effects encountered.

ANKL is treated similarly to most B-cell lymphomas. Anthracycline-containing chemotherapy regimens are commonly offered as the initial therapy. Some patients may receive a stem cell transplant.

Most patients will die 2 years after diagnosis.

As described above, chloromas should always be considered manifestations of systemic disease, rather than isolated local phenomena, and treated as such. In the patient with newly diagnosed leukemia and an associated chloroma, systemic chemotherapy against the leukemia is typically used as the first-line treatment, unless an indication for local treatment of the chloroma (e.g. compromise of the spinal cord) emerges. Chloromas are typically quite sensitive to standard antileukemic chemotherapy. Allogeneic hematopoietic stem cell transplantation should be considered in fit patients with suitable available donor, as long term remissions have been reported.

If the chloroma is persistent after completion of induction chemotherapy, local treatment, such as surgery or radiation therapy, may be considered, although neither has an effect on survival.

Patients presenting with a primary chloroma typically receive systemic chemotherapy, as development of acute leukemia is nearly universal in the short term after detection of the chloroma.

Patients treated for acute leukemia who relapse with an isolated chloroma are typically treated with systemic therapy for relapsed leukemia. However, as with any relapsed leukemia, outcomes are unfortunately poor.

Patients with "preleukemic" conditions, such as myelodysplastic syndromes or myeloproliferative syndromes, who develop a chloroma are often treated as if they have transformed to acute leukemia.

Acute mast cell leukemia is extremely aggressive and has a grave prognosis. In most cases, multi-organ failure including bone marrow failure develops over weeks to months. Median survival after diagnosis is only about 6 months.

Since leukostais/ hyperleukostasis is associated with leukemia, preventative treatments are put into action upon diagnosis.

Patients with hyerleukocystois associated with leukemia are always considered candidates for tumor lysis syndrome prophylaxis in addition to aggressive intravenous hydration with allopurinol or rasburicase to decrease serum uric acid levels.

Childhood leukemia is a very taxing disease, on the caregiver and the child. The emotional distress and post traumatic stress which it causes is very deep; studies show that only 3% of parents have to deal with their child becoming severely ill. It is common to experience stress, depression, and anxiety throughout and after cancer treatment.

Many people find it helpful to talk about their feelings with family and friends, health professionals, other patients, members of the clergy, and counselors or therapists. Being part of a support group can provide another outlet for people to share their feelings. Relaxation techniques, such as guided imagery and slow rhythmic breathing, can also help to ease negative thoughts or feelings. Reaching out to others, by participating in volunteer activities, can help people to feel stronger and more in control.

Treatment is directed toward the underlying cause. However, in primary eosinophilia, or if the eosinophil count must be lowered, corticosteroids such as prednisone may be used. However, immune suppression, the mechanism of action of corticosteroids, can be fatal in patients with parasitosis.

Treatment includes utilization of prophylactic methods in the event that the patient has been diagnosed with hyperleukocystosis. This is usually in combination with other treatments which are dependent on the type of leukemia. Specific treatments include lysis syndrome treatment in addition to aggressive intravenous hydration with allopurinol or rasburicase to decrease serum uric acid levels.

Since a primary cause of leukocystatis is caused by leukemia, surgery is often a treatment and dependent on tumor size and location.

Hematopoietic cell transplants are critical to correct leukostasis and leukemia.

Cytoreduction is also a critical course of treatment in order to rapidly decrease white blood cell counts. Twenty to forty percent of patients diagnosed with hyperkeuckocytosis die within the first week of symptom presentation. Patients with the best outcome have none or limited symptoms of respiratory or neurological distress. An accumulation of these symptoms leads to decreased levels of statistical survival compared to patients diagnosed with asymptomatic hyperleukocytosis alone.

Cytoreduction methods include chemotherapy, utilizing the drug hydroxyurea ( Hydroxyurea is usually used in asymptomatic hyperleukocytosis), and the less common leukapheresis procedure. This procedure is often utilized for asymptomatic hyperleuckocytosis patients who have induction chemotherapy postponed for patient specific factors.

Variants of Chemotherapy, including induction chemotherapy, are used to treat both elevated white blood cells counts while simultaneously targeting leukemia cells in bone marrow.

Prognosis of patients suffering from hyperleukocytosis is dependent on the cause and type of leukemia the patient has. Patients diagnosed with asymptomatic hyerpleukocytosis have significantly better survival rates than symptomatic hyperleuckocytosis (leukostasis). Preventative measures and contentious monitoring of patients diagnosed with leukemia is critical in receiving treatment as early as possible to prevent and treat hyperleuckocytosis.