alkeran
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Synonyms | |||
Melphalan, commercially known as Alkeran, is an alkylating chemotherapeutic agent derived from nitrogen mustard. It’s primarily used in the treatment of multiple myeloma and ovarian carcinoma, though it has applications in other malignancies and conditioning regimens for hematopoietic stem cell transplantation. As an oral or intravenous formulation, its mechanism involves cross-linking DNA strands, preventing cellular replication—particularly effective against rapidly dividing cancer cells. We initially struggled with its narrow therapeutic index; the difference between effective and toxic doses is perilously small, requiring meticulous dosing based on body surface area or ideal body weight.
Key Components and Bioavailability of Alkeran
The active pharmaceutical ingredient is melphalan itself—a phenylalanine derivative of mechlorethamine. This structure allows selective uptake by tumor cells expressing amino acid transporters, though selectivity isn’t absolute. We’ve observed significant interpatient variability in bioavailability with the oral formulation—anywhere from 25% to 89% absorption. Food, particularly high-fat meals, drastically reduces absorption, necessitating strict fasting administration. The intravenous form bypasses this unpredictability but introduces different challenges with stability—the solution requires immediate use after reconstitution.
Our pharmacy team constantly debates the optimal formulation. Dr. Chen in oncology insists IV is superior for predictable dosing in transplant protocols, while I’ve seen adequate responses with oral in outpatient palliative settings. The drug undergoes spontaneous hydrolysis in aqueous solutions and has variable hepatic metabolism, with about 30% protein binding. Renal excretion is primary—about 30% of IV dose appears unchanged in urine within 24 hours—making renal function critical in dosing decisions.
Mechanism of Action: Scientific Substantiation
Alkeran works through bifunctional alkylation, forming covalent bonds with the N7 position of guanine bases in DNA. This creates intra-strand and inter-strand crosslinks that disrupt DNA replication and transcription. The phenylalanine moiety theoretically facilitates transport into cells via amino acid carriers, though in practice we see significant uptake in normal tissues too—hence the bone marrow suppression.
What’s fascinating clinically is how this mechanism plays out differently across malignancies. In multiple myeloma, which has relatively slow proliferation compared to acute leukemias, the cumulative DNA damage eventually overwhelms the cancer cell’s repair mechanisms. We initially thought it was purely about replication interference, but there’s emerging evidence of immunogenic cell death components—melphalan-treated cells release damage-associated molecular patterns that stimulate antitumor immunity.
The biochemical process involves formation of highly reactive aziridinium intermediates that attack nucleophilic sites. This happens more readily at physiological pH, which is why reconstituted solutions degrade so rapidly. I remember our first protocol for intraperitoneal administration in ovarian cancer—we had to administer within 30 minutes of preparation, racing against the clock as the drug lost potency.
Indications for Use: What is Alkeran Effective For?
Alkeran for Multiple Myeloma
This remains the primary indication where it shows the most consistent efficacy. As first-line therapy in transplant-eligible patients, high-dose IV melphalan (200 mg/m²) with autologous stem cell support produces response rates of 60-80%. In elderly or transplant-ineligible patients, we use lower oral doses (0.25 mg/kg daily for 4 days monthly) in combination with prednisone, with median survival around 3-4 years.
Alkeran for Ovarian Carcinoma
Particularly in the palliative setting for platinum-resistant disease. The response rates are modest—15-20%—but meaningful for symptom control. We’ve had better outcomes with intraperitoneal administration in select patients with minimal residual disease after debulking.
Alkeran for Neuroblastoma
High-dose regimens with stem cell rescue in pediatric patients with high-risk disease. The challenge here is the delicate balance in children—we dose based on weight rather than surface area and monitor even more closely for hepatic veno-occlusive disease.
Alkeran for Amyloidosis
As conditioning before autologous stem cell transplantation in selected AL amyloidosis patients. This requires extreme caution given frequent multi-organ involvement and heightened treatment-related mortality.
Alkeran for Other Conditions
We’ve occasionally used it in Waldensström’s macroglobulinemia, polycythemia vera, and as part of reduced-intensity conditioning regimens for allogeneic transplantation in elderly patients.
Instructions for Use: Dosage and Course of Administration
Dosing is highly indication-dependent and requires individualization. For multiple myeloma, we typically follow these protocols:
| Indication | Dosage | Frequency | Duration/Schedule | Administration Notes |
|---|---|---|---|---|
| Multiple myeloma (oral) | 0.15 mg/kg/day | Daily | 7 days, then 2-3 weeks rest | Fasting state, monitor blood counts weekly |
| Multiple myeloma (high-dose IV) | 200 mg/m² | Single dose | Pre-transplant conditioning | With autologous stem cell support, antiemetics essential |
| Ovarian cancer (oral) | 0.2 mg/kg/day | Daily | 5 days monthly | Fasting, adjust for hematologic toxicity |
The course typically continues until disease progression or unacceptable toxicity. We monitor complete blood counts weekly during initial cycles, then biweekly once stable. Dose reductions of 25-50% are common for hematologic toxicity.
For the high-dose transplant regimen, we administer as a 30-minute IV infusion after premedication with antiemetics. The oral formulation should be taken on an empty stomach—at least 1 hour before or 2 hours after meals—as food reduces bioavailability by up to 50%.
Contraindications and Drug Interactions
Absolute contraindications include hypersensitivity to melphalan, severe bone marrow suppression prior to treatment (unless part of transplant conditioning), and pregnancy. We’re particularly cautious with renal impairment—dose reduction is essential when creatinine clearance falls below 60 mL/min.
Significant drug interactions occur with:
- Live vaccines - contraindicated due to immunosuppression
- Nephrotoxic agents (aminoglycosides, NSAIDs) - increased toxicity risk
- Cimetidine - may reduce bioavailability of oral melphalan
- Cyclosporine - increased risk of renal toxicity
We had a case where a patient on maintenance therapy started high-dose ibuprofen for arthritis and developed pancytopenia—the combination apparently impaired renal clearance enough to elevate melphalan levels dangerously.
The most concerning adverse effects are hematologic—myelosuppression typically nadirs around 2-3 weeks after administration. We’ve seen delayed marrow recovery in older patients, sometimes taking 6-8 weeks. Secondary malignancies, particularly acute myeloid leukemia, occur in 2-5% of long-term survivors, typically 3-5 years after treatment.
Clinical Studies and Evidence Base
The landmark IFM 90 trial established high-dose melphalan with autologous stem cell transplantation as standard for eligible myeloma patients, demonstrating superior overall survival compared to conventional chemotherapy. More recently, the FIRST trial showed lenalidomide-dexamethasone outperforms melphalan-prednisone-thalidomide in transplant-ineligible patients, though melphalan regimens remain relevant in resource-limited settings.
For ovarian cancer, the GOG-111 study initially established platinum-paclitaxel as superior, but melphalan maintains a role in salvage therapy. A 2018 meta-analysis in Gynecologic Oncology confirmed response rates of 18% in platinum-resistant disease.
What the trials don’t capture well is the real-world variability. I’ve seen patients tolerate full doses with minimal toxicity at 75, while others half their age require 50% reductions. We’re increasingly using pharmacogenetic testing to identify slow metabolizers who might benefit from preemptive dose adjustment.
Comparing Alkeran with Similar Products and Choosing Quality
Among alkylating agents, melphalan occupies a specific niche compared to cyclophosphamide (better for lymphomas, more urotoxic) and bendamustine (increasingly used in CLL and lymphomas). The oral bioavailability distinguishes it from many IV-only alternatives.
When sourcing, we insist on FDA-approved manufacturers and avoid compounding pharmacies for the oral formulation after an incident with inconsistent bioavailability from a local compounder. The tablets should be stored properly—room temperature, protected from light and moisture. We’ve observed potency loss in improperly stored medication, particularly in humid climates.
For IV formulation, we verify the lot number and expiration date meticulously and administer immediately after reconstitution. The solution should be clear—any discoloration or precipitation indicates degradation.
Frequently Asked Questions
What monitoring is required during Alkeran treatment?
Weekly CBC with differential for at least the first two cycles, then every 2-4 weeks. Liver and renal function monthly. More frequent monitoring in elderly patients or those with organ dysfunction.
How long does it take to see response in multiple myeloma?
M-protein reduction typically begins within the first cycle, with maximal response by 3-6 months in most patients. We measure serum free light chains monthly to track response.
Can Alkeran be used in renal impairment?
Yes, but with dose reduction. We typically reduce by 25% for CrCl 30-60 mL/min and 50% for CrCl <30 mL/min. In dialysis patients, we administer after dialysis sessions.
What supportive care is needed?
Antiemetics for IV administration, growth factor support for persistent neutropenia, transfusion support for anemia/thrombocytopenia, and infection prophylaxis in high-risk patients.
Are there genetic factors affecting response?
Emerging evidence suggests polymorphisms in glutathione S-transferases may influence toxicity and efficacy, though routine testing isn’t yet standard.
Conclusion: Validity of Alkeran Use in Clinical Practice
Despite newer agents, Alkeran maintains an important role in hematologic malignancies, particularly multiple myeloma and amyloidosis. The risk-benefit profile favors use in carefully selected patients with appropriate monitoring. For transplant-eligible myeloma patients, high-dose melphalan remains the backbone of conditioning regimens. In palliative settings, oral melphalan provides reasonable disease control with manageable toxicity when properly dosed.
I remember Mrs. Gable—72-year-old with IgG kappa myeloma, not a transplant candidate. We started her on melphalan-prednisone back in 2015. She had moderate cytopenias but achieved a very good partial response that lasted nearly four years. She eventually progressed and switched to lenalidomide, but those were good quality years where she saw two grandchildren born and traveled with her husband. Meanwhile, Mr. Davies, only 58, developed treatment-related AML after three years of melphalan for his myeloma—a devastating outcome that reminds us of the double-edged sword.
The pharmacy and clinical teams still debate optimal dosing strategies—particularly whether we should be more aggressive with prophylactic growth factors to maintain dose intensity. Our current compromise is to individualize based on age, performance status, and treatment goals. What’s clear after decades of use is that melphalan, while old-fashioned, isn’t obsolete—it just requires respect for its narrow therapeutic window and potentially severe toxicities. Proper patient selection, meticulous dosing, and vigilant monitoring remain paramount.